Baroreflex activation therapy with conditional shut off

ABSTRACT

An aspect of the present subject matter relates to a baroreflex stimulator. An embodiment of the stimulator comprises a pulse generator to provide a baroreflex stimulation signal through an electrode, and a modulator to modulate the baroreflex stimulation signal based on a circadian rhythm template. Other aspects are provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 12/749,939, filed Mar. 30, 2010, which is adivisional application of U.S. application Ser. No. 10/746,844, filedDec. 24, 2003, published as US 2005/0149130 on Jul. 7, 2005, now U.S.Pat. No. 7,706,884, both of which are herein incorporated by referencein their entirety.

This application is a continuation-in-part application of U.S.application Ser. No. 11/000,249, filed Nov. 30, 2004, published as US2006/0116737 on Jun. 1, 2006, which is herein incorporated by referencein its entirety.

This application is a continuation-in-part application of U.S.application Ser. No. 11/279,188, filed Apr. 10, 2006, published as US2007/0239210 on Oct. 11, 2007, which is herein incorporated by referencein its entirety.

This application is a continuation-in-part application of U.S.application Ser. No. 11/459,481, filed Jul. 24, 2006, published as US2008/0021504 on Jan. 24, 2008, which is herein incorporated by referencein its entirety.

This application is also related to U.S. application Ser. No.10/864,070, filed Jun. 8, 2004, now U.S. Pat. No. 7,194,313, which wasfiled as a divisional of U.S. application Ser. No. 10/746,844, both ofwhich are incorporated by reference in their entirety.

The following commonly assigned U.S. patent applications are related,are all filed on Dec. 24, 2003 and are all herein incorporated byreference in their entirety: “Baroreflex Stimulation System to ReduceHypertension,” U.S. patent application Ser. No. 10/746,134, published asUS 2005/0149128 on Jul. 7, 2005, now U.S. Pat. No. 7,643,875; “SensingWith Compensation for Neural Stimulator,” U.S. patent application Ser.No. 10/746,847, published as US 2005/0149133 on Jul. 7, 2005;“Implantable Baroreflex Stimulator with Integrated Pressure Sensor,”U.S. patent application Ser. No. 10/745,921, published as US2005/0149143 on Jul. 7, 2005; “Automatic Baroreflex Modulation Based onCardiac Activity,” U.S. patent application Ser. No. 10/746,846,published as US 2005/0149132 on Jul. 7, 2005; “Automatic BaroreflexModulation Responsive to Adverse Event,” U.S. patent application Ser.No. 10/745,925, published as US 2005/0149127 on Jul. 7, 2005, now U.S.Pat. No. 7,509,166; “Baroreflex Modulation to Gradually Increase BloodPressure,” U.S. patent application Ser. No. 10/746,845, published as US2005/0149131 on Jul. 7, 2005, now U.S. Pat. No. 7,486,991; “BaroreflexStimulation to Treat Acute Myocardial Infarction,” U.S. patentapplication Ser. No. 10/745,920, published as US 2005/0149126 on Jul. 7,2005, now U.S. Pat. No. 7,460,906; “Baropacing and Cardiac Pacing toControl Output,” U.S. patent application Ser. No. 10/746,135, publishedas US 2005/0149129 on Jul. 7, 2005; “A Lead for Stimulating theBaroreflex in the Pulmonary Artery,” U.S. patent application Ser. No.10/746,861, published as US 2005/0149156 on Jul. 7, 2005; and “AStimulation Lead for Stimulating the Baroreceptors in the PulmonaryArtery,” U.S. patent application Ser. No. 10/746,852, published as2005/0149155 on Jul. 7, 2005.

TECHNICAL FIELD

This application relates generally to implantable medical devices and,more particularly, to synchronizing baroreflex stimulation to circadianrhythm.

BACKGROUND

Implanting a chronic electrical stimulator, such as a cardiacstimulator, to deliver medical therapy(ies) is known. Examples ofcardiac stimulators include implantable cardiac rhythm management (CRM)device such as pacemakers, implantable cardiac defibrillators (ICDs),and implantable devices capable of performing pacing and defibrillatingfunctions.

CRM devices are implantable devices that provide electrical stimulationto selected chambers of the heart in order to treat disorders of cardiacrhythm. An implantable pacemaker, for example, is a CRM device thatpaces the heart with timed pacing pulses. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Some CRM devices synchronize pacing pulses deliveredto different areas of the heart in order to coordinate the contractions.Coordinated contractions allow the heart to pump efficiently whileproviding sufficient cardiac output.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

A pressoreceptive region or field is capable of sensing changes inpressure, such as changes in blood pressure. Pressoreceptor regions arereferred to herein as baroreceptors, which generally include any sensorsof pressure changes. For example, baroreceptors include afferent nervesand further include sensory nerve endings that are sensitive to thestretching of the wall that results from increased blood pressure fromwithin, and function as the receptor of a central reflex mechanism thattends to reduce the pressure. Baroreflex functions as a negativefeedback system, and relates to a reflex mechanism triggered bystimulation of a baroreceptor. Increased pressure stretches bloodvessels, which in turn activates baroreceptors in the vessel walls.Activation of baroreceptors naturally occurs through internal pressureand stretching of the arterial wall, causing baroreflex inhibition ofsympathetic nerve activity (SNA) and a reduction in systemic arterialpressure. An increase in baroreceptor activity induces a reduction ofSNA, which reduces blood pressure by decreasing peripheral vascularresistance.

The general concept of stimulating afferent nerve trunks leading frombaroreceptors is known. For example, direct electrical stimulation hasbeen applied to the vagal nerve and carotid sinus. Research hasindicated that electrical stimulation of the carotid sinus nerve canresult in reduction of experimental hypertension, and that directelectrical stimulation to the pressoreceptive regions of the carotidsinus itself brings about reflex reduction in experimental hypertension.

Electrical systems have been proposed to treat hypertension in patientswho do not otherwise respond to therapy involving lifestyle changes andhypertension drugs, and possibly to reduce drug dependency for otherpatients.

SUMMARY

Various aspects and embodiments of the present subject matter providebaroreflex stimulation that mimics the natural circadian rhythm byproviding stimulation levels that rise and fall during the day. Suchstimulation, for example, promotes sleep or rest during certain portionsof the day and promotes activity during other portions of the day.

An aspect of the present subject matter relates to a baroreflexstimulator. An embodiment of the stimulator comprises a pulse generatorto provide a baroreflex stimulation signal through an electrode, and amodulator to modulate the baroreflex stimulation signal based on acircadian rhythm template.

An aspect of the present subject matter relates to a baroreflexstimulator. An embodiment of the stimulator comprises a pulse generatorto provide a baroreflex stimulation signal through an electrode, andmeans for modulating the baroreflex stimulation signal based on acircadian rhythm.

An aspect of the present subject matter relates to a method foroperating an implantable medical device. In an embodiment, a baroreflexstimulation therapy is applied using a baroreflex stimulator in theimplantable medical device. The baroreflex stimulation therapy ismodulated based on a circadian rhythm template. In one methodembodiment, a circadian rhythm template is accessed, a baroreflexstimulation level is set based on the circadian rhythm template.Baroreflex stimulation is applied at the baroreflex stimulation level toa baroreceptor site in a pulmonary artery.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol.

FIGS. 2A-2C illustrate a heart.

FIG. 3 illustrates baroreceptors and afferent nerves in the area of thecarotid sinuses and aortic arch.

FIG. 4 illustrates baroreceptors in and around the pulmonary artery.

FIG. 5 illustrates baroreceptor fields in the aortic arch, theligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 6 illustrates a known relationship between respiration and bloodpressure when the baroreflex is stimulated.

FIG. 7 illustrates a blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation.

FIG. 8 illustrates a system including an implantable medical device(IMD) and a programmer, according to various embodiments of the presentsubject matter.

FIG. 9 illustrates an implantable medical device (IMD) such as shown inthe system of FIG. 8, according to various embodiments of the presentsubject matter.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter.

FIG. 11 illustrates an implantable medical device (IMD) such as shown inFIG. 8 having a neural stimulator (NS) component and cardiac rhythmmanagement (CRM) component, according to various embodiments of thepresent subject matter.

FIG. 12 illustrates a system including a programmer, an implantableneural stimulator (NS) device and an implantable cardiac rhythmmanagement (CRM) device, according to various embodiments of the presentsubject matter.

FIG. 13 illustrates an implantable neural stimulator (NS) device such asshown in the system of FIG. 12, according to various embodiments of thepresent subject matter.

FIG. 14 illustrates an implantable cardiac rhythm management (CRM)device such as shown in the system of FIG. 12, according to variousembodiments of the present subject matter.

FIG. 15 illustrates a programmer such as illustrated in the systems ofFIGS. 8 and 12 or other external device to communicate with theimplantable medical device(s), according to various embodiments of thepresent subject matter.

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from a neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter.

FIG. 17 illustrates a system to modulate baroreflex stimulation,according to various embodiments of the present subject matter.

FIGS. 18A-18C illustrate methods for modulating baroreceptor stimulationbased on a cardiac activity parameter, according to various embodimentsof the present subject matter.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter.

FIGS. 20A-20B illustrate methods for modulating baroreceptor stimulationbased on detection of an adverse event, according to various embodimentsof the present subject matter.

FIGS. 21A-21E illustrate circadian rhythm.

FIG. 22 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter.

FIG. 23A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter.

FIG. 24 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter.

FIGS. 25A-25B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter.

FIG. 26 is a block diagram illustrating an embodiment of a circuit of aneural stimulation system.

FIG. 27 illustrates an embodiment of a therapy titration module.

FIG. 28 illustrates an implantable medical device (IMD), according tovarious embodiments of the present subject matter.

FIG. 29 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 30 is a block diagram illustrating an embodiment of an externalsystem.

FIG. 31 illustrates a system embodiment in which an IMD is placedsubcutaneously or submuscularly in a patient's chest with lead(s)positioned to stimulate a vagus nerve.

FIG. 32 illustrates a system embodiment that includes an implantablemedical device (IMD) with satellite electrode(s) positioned to stimulateat least one neural target.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Hypertension and Baroreflex Physiology

A brief discussion of hypertension and the physiology related tobaroreceptors is provided to assist the reader with understanding thisdisclosure. This brief discussion introduces hypertension, the autonomicnervous system, and baroreflex.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension generally relates to high blood pressure,such as a transitory or sustained elevation of systemic arterial bloodpressure to a level that is likely to induce cardiovascular damage orother adverse consequences. Hypertension has been arbitrarily defined asa systolic blood pressure above 140 mm Hg or a diastolic blood pressureabove 90 mm Hg. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure. Consequences of uncontrolled hypertension include, but are notlimited to, retinal vascular disease and stroke, left ventricularhypertrophy and failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes, but is not limited to, the sympathetic nervous systemand the parasympathetic nervous system. The sympathetic nervous systemis affiliated with stress and the “fight or flight response” toemergencies. Among other effects, the “fight or flight response”increases blood pressure and heart rate to increase skeletal muscleblood flow, and decreases digestion to provide the energy for “fightingor fleeing.” The parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response” which, among othereffects, decreases blood pressure and heart rate, and increasesdigestion to conserve energy. The ANS maintains normal internal functionand works with the somatic nervous system.

The subject matter of this disclosure generally refers to the effectsthat the ANS has on the heart rate and blood pressure, includingvasodilation and vasoconstriction. The heart rate and force is increasedwhen the sympathetic nervous system is stimulated, and is decreased whenthe sympathetic nervous system is inhibited (the parasympathetic nervoussystem is stimulated). FIGS. 1A and 1B illustrate neural mechanisms forperipheral vascular control. FIG. 1A generally illustrates afferentnerves to vasomotor centers. An afferent nerve conveys impulses toward anerve center. A vasomotor center relates to nerves that dilate andconstrict blood vessels to control the size of the blood vessels. FIG.1B generally illustrates efferent nerves from vasomotor centers. Anefferent nerve conveys impulses away from a nerve center.

Stimulating the systematic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, and increases digestion in the smallintention, increases urine secretion, and contracts the wall and relaxesthe sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other. Thus, an indiscriminatestimulation of the sympathetic and/or parasympathetic nervous systems toachieve a desired response, such as vasodilation, in one physiologicalsystem may also result in an undesired response in other physiologicalsystems.

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, cardiac fatpads, vena cava, aortic arch and carotid sinus, that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Additionally, a baroreceptor includesafferent nerve trunks, such as the vagus, aortic and carotid nerves,leading from the sensory nerve endings. Stimulating baroreceptorsinhibits sympathetic nerve activity (stimulates the parasympatheticnervous system) and reduces systemic arterial pressure by decreasingperipheral vascular resistance and cardiac contractility. Baroreceptorsare naturally stimulated by internal pressure and the stretching of thearterial wall.

Some aspects of the present subject matter locally stimulate specificnerve endings in arterial walls rather than stimulate afferent nervetrunks in an effort to stimulate a desire response (e.g. reducedhypertension) while reducing the undesired effects of indiscriminatestimulation of the nervous system. For example, some embodimentsstimulate baroreceptor sites in the pulmonary artery. Some embodimentsof the present subject matter involve stimulating either baroreceptorsites or nerve endings in the aorta, the chambers of the heart, the fatpads of the heart, and some embodiments of the present subject matterinvolve stimulating an afferent nerve trunk, such as the vagus, carotidand aortic nerves. Some embodiments stimulate afferent nerve trunksusing a cuff electrode, and some embodiments stimulate afferent nervetrunks using an intravascular lead positioned in a blood vesselproximate to the nerve, such that the electrical stimulation passesthrough the vessel wall to stimulate the afferent nerve trunk.

FIGS. 2A-2C illustrate a heart. As illustrated in FIG. 2A, the heart 201includes a superior vena cava 202, an aortic arch 203, and a pulmonaryartery 204, and is useful to provide a contextual relationship with theillustrations in FIGS. 3-5. As is discussed in more detail below, thepulmonary artery 204 includes baroreceptors. A lead is capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacemaker lead, and continuefrom the right ventricle through the pulmonary valve into the pulmonaryartery. A portion of the pulmonary artery and aorta are proximate toeach other. Various embodiments stimulate baroreceptors in the aortausing a lead intravascularly positioned in the pulmonary artery. Thus,according to various aspects of the present subject matter, thebaroreflex is stimulated in or around the pulmonary artery by at leastone electrode intravascularly inserted into the pulmonary artery.Alternatively, a wireless stimulating device, with or without pressuresensing capability, may be positioned via catheter into the pulmonaryartery. Control of stimulation and/or energy for stimulation may besupplied by another implantable or external device via ultrasonic,electromagnetic or a combination thereof. Aspects of the present subjectmatter provide a relatively noninvasive surgical technique to implant abaroreceptor stimulator intravascularly into the pulmonary artery.

FIGS. 2B-2C illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which have nerveendings that function as baroreceptor sites. FIG. 2B illustrates theright atrium 267, right ventricle 268, sinoatrial node 269, superiorvena cava 202, inferior vena cava 270, aorta 271, right pulmonary veins272, and right pulmonary artery 273. FIG. 2B also illustrates a cardiacfat pad 274 between the superior vena cava and aorta. Baroreceptor nerveendings in the cardiac fat pad 274 are stimulated in some embodimentsusing an electrode screwed into the fat pad, and are stimulated in someembodiments using an intravenously-fed lead proximately positioned tothe fat pad in a vessel such as the right pulmonary artery or superiorvena cava, for example. FIG. 2C illustrates the left atrium 275, leftventricle 276, right atrium 267, right ventricle 268, superior vena cava202, inferior vena cava 270, aorta 271, right pulmonary veins 272, leftpulmonary vein 277, right pulmonary artery 273, and coronary sinus 278.FIG. 2C also illustrates a cardiac fat pad 279 located proximate to theright cardiac veins and a cardiac fat pad 280 located proximate to theinferior vena cava and left atrium. Baroreceptor nerve endings in thefat pad 279 are stimulated in some embodiments using an electrodescrewed into the fat pad 279, and are stimulated in some embodimentsusing an intravenously-fed lead proximately positioned to the fat pad ina vessel such as the right pulmonary artery 273 or right pulmonary vein272, for example. Baroreceptors in the 280 are stimulated in someembodiments using an electrode screwed into the fat pad, and arestimulated in some embodiments using an intravenously-fed leadproximately positioned to the fat pad in a vessel such as the inferiorvena cava 270 or coronary sinus or a lead in the left atrium 275, forexample.

FIG. 3 illustrates baroreceptors in the area of the carotid sinuses 305,aortic arch 303 and pulmonary artery 304. The aortic arch 303 andpulmonary artery 304 were previously illustrated with respect to theheart in FIG. 2A. As illustrated in FIG. 3, the vagus nerve 306 extendsand provides sensory nerve endings 307 that function as baroreceptors inthe aortic arch 303, in the carotid sinus 305 and in the common carotidartery 310. The glossopharyngeal nerve 308 provides nerve endings 309that function as baroreceptors in the carotid sinus 305. These nerveendings 307 and 309, for example, are sensitive to stretching of thewall resulting from increased pressure from within. Activation of thesenerve endings reduce pressure. Although not illustrated in the figures,the fat pads and the atrial and ventricular chambers of the heart alsoinclude baroreceptors. Cuffs have been placed around afferent nervetrunks, such as the vagal nerve, leading from baroreceptors to vasomotorcenters to stimulate the baroreflex. According to various embodiments ofthe present subject matter, afferent nerve trunks can be stimulatedusing a cuff or intravascularly-fed lead positioned in a blood vesselproximate to the afferent nerves.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery 404.The superior vena cava 402 and the aortic arch 403 are also illustrated.As illustrated, the pulmonary artery 404 includes a number ofbaroreceptors 411, as generally indicated by the dark area. Furthermore,a cluster of closely spaced baroreceptors is situated near theattachment of the ligamentum arteriosum 412. FIG. 4 also illustrates theright ventricle 413 of the heart, and the pulmonary valve 414 separatingthe right ventricle 413 from the pulmonary artery 404. According tovarious embodiments of the present subject matter, a lead is insertedthrough a peripheral vein and threaded through the tricuspid valve intothe right ventricle, and from the right ventricle 413 through thepulmonary valve 414 and into the pulmonary artery 404 to stimulatebaroreceptors in and/or around the pulmonary artery. In variousembodiments, for example, the lead is positioned to stimulate thecluster of baroreceptors near the ligamentum arteriosum 412. FIG. 5illustrates baroreceptor fields 511 in the aortic arch 503, near theligamentum arteriosum 512 and the trunk of the pulmonary artery 504.Some embodiments position the lead in the pulmonary artery to stimulatebaroreceptor sites in the aorta and/or fat pads, such as are illustratedin FIGS. 2B-2C.

FIG. 6 illustrates a known relationship between respiration 615 andblood pressure 616 when the left aortic nerve is stimulated. When thenerve is stimulated at 617, the blood pressure 616 drops, and therespiration 615 becomes faster and deeper, as illustrated by the higherfrequency and amplitude of the respiration waveform. The respiration andblood pressure appear to return to the pre-stimulated state inapproximately one to two minutes after the stimulation is removed.Various embodiments of the present subject matter use this relationshipbetween respiration and blood pressure by using respiration as asurrogate parameter for blood pressure.

FIG. 7 illustrates a known blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation. The figure illustrates that the bloodpressure of a stimulated dog 718 is significantly less than the bloodpressure of a control dog 719 that also has high blood pressure. Thus,intermittent stimulation is capable of triggering the baroreflex toreduce high blood pressure.

Baroreflex Stimulator Systems

Various embodiments of the present subject matter relate to baroreflexstimulator systems. Such baroreflex stimulation systems are alsoreferred to herein as neural stimulator (NS) devices or components.Examples of neural stimulators include anti-hypertension (AHT) devicesor AHT components that are used to treat hypertension. Variousembodiments of the present subject matter include stand-aloneimplantable baroreceptor stimulator systems, include implantable devicesthat have integrated NS and cardiac rhythm management (CRM) components,and include systems with at least one implantable NS device and animplantable CRM device capable of communicating with each other eitherwirelessly or through a wire lead connecting the implantable devices.Integrating NS and CRM functions that are either performed in the sameor separate devices improves aspects of the NS therapy and cardiactherapy by allowing these therapies to work together intelligently.

FIG. 8 illustrates a system 820 including an implantable medical device(IMD) 821 and a programmer 822, according to various embodiments of thepresent subject matter. Various embodiments of the IMD 821 includeneural stimulator functions only, and various embodiments include acombination of NS and CRM functions. Some embodiments of the neuralstimulator provide AHT functions. The programmer 822 and the IMD 821 arecapable of wirelessly communicating data and instructions. In variousembodiments, for example, the programmer 822 and IMD 821 use telemetrycoils to wirelessly communicate data and instructions. Thus, theprogrammer can be used to adjust the programmed therapy provided by theIMD 821, and the IMD can report device data (such as battery and leadresistance) and therapy data (such as sense and stimulation data) to theprogrammer using radio telemetry, for example. According to variousembodiments, the IMD 821 stimulates baroreceptors to provide NS therapysuch as AHT therapy. Various embodiments of the IMD 821 stimulatebaroreceptors in the pulmonary artery using a lead fed through the rightventricle similar to a cardiac pacemaker lead, and further fed into thepulmonary artery. According to various embodiments, the IMD 821 includesa sensor to sense ANS activity. Such a sensor can be used to performfeedback in a closed loop control system. For example, variousembodiments sense surrogate parameters, such as respiration and bloodpressure, indicative of ANS activity. According to various embodiments,the IMD further includes cardiac stimulation capabilities, such aspacing and defibrillating capabilities in addition to the capabilitiesto stimulate baroreceptors and/or sense ANS activity.

FIG. 9 illustrates an implantable medical device (IMD) 921 such as theIMD 821 shown in the system 820 of FIG. 8, according to variousembodiments of the present subject matter. The illustrated IMD 921performs NS functions. Some embodiments of the illustrated IMD 921performs an AHT function, and thus illustrates an implantable AHTdevice. The illustrated device 921 includes controller circuitry 923 anda memory 924. The controller circuitry 923 is capable of beingimplemented using hardware, software, and combinations of hardware andsoftware. For example, according to various embodiments, the controllercircuitry 923 includes a processor to perform instructions embedded inthe memory 924 to perform functions associated with NS therapy such asAHT therapy. For example, the illustrated device 921 further includes atransceiver 925 and associated circuitry for use to communicate with aprogrammer or another external or internal device. Various embodimentshave wireless communication capabilities. For example, some transceiverembodiments use a telemetry coil to wirelessly communicate with aprogrammer or another external or internal device.

The illustrated device 921 further includes baroreceptor stimulationcircuitry 926. Various embodiments of the device 921 also includessensor circuitry 927. One or more leads are able to be connected to thesensor circuitry 927 and baroreceptor stimulation circuitry 926. Thebaroreceptor stimulation circuitry 926 is used to apply electricalstimulation pulses to desired baroreceptors sites, such as baroreceptorsites in the pulmonary artery, through one or more stimulationelectrodes. The sensor circuitry 927 is used to detect and process ANSnerve activity and/or surrogate parameters such as blood pressure,respiration and the like, to determine the ANS activity.

According to various embodiments, the stimulator circuitry 926 includesmodules to set any one or any combination of two or more of thefollowing pulse features: the amplitude 928 of the stimulation pulse,the frequency 929 of the stimulation pulse, the burst frequency 930 orduty cycle of the pulse, and the wave morphology 931 of the pulse.Examples of wave morphology include a square wave, triangle wave,sinusoidal wave, and waves with desired harmonic components to mimicwhite noise such as is indicative of naturally-occurring baroreflexstimulation.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter. Although not drawn to scale, theseillustrated leads 1032A, 1032B and 1032C include an IPS 1033 with abaroreceptor stimulator electrode 1034 to monitor changes in bloodpressure, and thus the effect of the baroreceptor stimulation. Theselead illustrations should not be read as limiting other aspects andembodiments of the present subject matter. In various embodiments, forexample, micro-electrical mechanical systems (MEMS) technology is usedto sense the blood pressure. Some sensor embodiments determine bloodpressure based on a displacement of a membrane.

FIGS. 10A-10C illustrate an IPS on a lead. Some embodiments implant anIPS in an IMD or NS device. The stimulator and sensor functions can beintegrated, even if the stimulator and sensors are located in separateleads or positions.

The lead 1032A illustrated in FIG. 10A includes a distally-positionedbaroreceptor stimulator electrode 1034 and an IPS 1033. This lead, forexample, is capable of being intravascularly introduced to stimulate abaroreceptor site, such as the baroreceptor sites in the pulmonaryartery, aortic arch, ligamentum arteriosum, the coronary sinus, in theatrial and ventricular chambers, and/or in cardiac fat pads.

The lead 1032B illustrated in FIG. 10B includes a tip electrode 1035, afirst ring electrode 1036, second ring electrode 1034, and an IPS 1033.This lead may be intravascularly inserted into or proximate to chambersof the heart and further positioned proximate to baroreceptor sites suchthat at least some of the electrodes 1035, 1036 and 1034 are capable ofbeing used to pace or otherwise stimulate the heart, and at least someof the electrodes are capable of stimulating at least one baroreceptorsite. The IPS 1033 is used to sense the blood pressure. In variousembodiments, the IPS is used to sense the blood pressure in the vesselproximate to the baroreceptor site selected for stimulation.

The lead 1032C illustrated in FIG. 10C includes a distally-positionedbaroreceptor stimulator electrode 1034, an IPS 1033 and a ring electrode1036. This lead 1032C may, for example, be intravascularly inserted intothe right atrium and ventricle, and then through the pulmonary valveinto the pulmonary artery. Depending on programming in the device, theelectrode 1036 can be used to pace and/or sense cardiac activity, suchas that which may occur within the right ventricle, and the electrode1034 and IPS 1033 are located near baroreceptors in or near thepulmonary artery to stimulate and sense, either directly or indirectlythrough surrogate parameters, baroreflex activity.

Thus, various embodiments of the present subject matter provide animplantable NS device that automatically modulates baroreceptorstimulation using an IPS. Integrating the pressure sensor into the leadprovides localized feedback for the stimulation. This localized sensingimproves feedback control. For example, the integrated sensor can beused to compensate for inertia of the baroreflex such that the target isnot continuously overshot. According to various embodiments, the devicemonitors pressure parameters such as mean arterial pressure, systolicpressure, diastolic pressure and the like. As mean arterial pressureincreases or remains above a programmable target pressure, for example,the device stimulates baroreceptors at an increased rate to reduce bloodpressure and control hypertension. As mean arterial pressure decreasestowards the target pressure, the device responds by reducingbaroreceptor stimulation. In various embodiments, the algorithm takesinto account the current metabolic state (cardiac demand) and adjustsneural stimulation accordingly. A NS device having an IPS is able toautomatically modulate baroreceptor stimulation, which allows animplantable NS device to determine the level of hypertension in thepatient and respond by delivering the appropriate level of therapy.However, it is noted that other sensors, including sensors that do notreside in an NS or neural stimulator device, can be used to provideclose loop feedback control.

FIG. 11 illustrates an implantable medical device (IMD) 1121 such asshown at 821 in FIG. 8 having an anti-hypertension (AHT) component 1137and cardiac rhythm management (CRM) component 1138, according to variousembodiments of the present subject matter. The illustrated device 1121includes a controller 1123 and a memory 1124. According to variousembodiments, the controller 1123 includes hardware, software, or acombination of hardware and software to perform the baroreceptorstimulation and CRM functions. For example, the programmed therapyapplications discussed in this disclosure are capable of being stored ascomputer-readable instructions embodied in memory and executed by aprocessor. According to various embodiments, the controller 1123includes a processor to execute instructions embedded in memory toperform the baroreceptor stimulation and CRM functions. The illustrateddevice 1121 further includes a transceiver and associated circuitry foruse to communicate with a programmer or another external or internaldevice. Various embodiments include a telemetry coil.

The CRM therapy section 1138 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The CRM therapy section includes a pulsegenerator 1139 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1140 to detect and process sensed cardiac signals. An interface 1141 isgenerally illustrated for use to communicate between the controller 1123and the pulse generator 1139 and sense circuitry 1140. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1137 includes components, under the control ofthe controller, to stimulate a baroreceptor and/or sense ANS parametersassociated with nerve activity or surrogates of ANS parameters such asblood pressure and respiration. Three interfaces 1142 are illustratedfor use to provide ANS therapy. However, the present subject matter isnot limited to a particular number interfaces, or to any particularstimulating or sensing functions. Pulse generators 1143 are used toprovide electrical pulses to an electrode for use to stimulate abaroreceptor site. According to various embodiments, the pulse generatorincludes circuitry to set, and in some embodiments change, the amplitudeof the stimulation pulse, the frequency of the stimulation pulse, theburst frequency of the pulse, and the morphology of the pulse such as asquare wave, triangle wave, sinusoidal wave, and waves with desiredharmonic components to mimic white noise or other signals. Sensecircuits 1144 are used to detect and process signals from a sensor, suchas a sensor of nerve activity, blood pressure, respiration, and thelike. The interfaces 1142 are generally illustrated for use tocommunicate between the controller 1123 and the pulse generator 1143 andsense circuitry 1144. Each interface, for example, may be used tocontrol a separate lead. Various embodiments of the NS therapy sectiononly include a pulse generator to stimulate baroreceptors. For example,the NS therapy section provides AHT therapy.

An aspect of the present subject matter relates to achronically-implanted stimulation system specially designed to treathypertension by monitoring blood pressure and stimulating baroreceptorsto activate the baroreceptor reflex and inhibit sympathetic dischargefrom the vasomotor center. Baroreceptors are located in variousanatomical locations such as the carotid sinus and the aortic arch.Other baroreceptor locations include the pulmonary artery, including theligamentum arteriosum, and sites in the atrial and ventricular chambers.In various embodiments, the system is integrated into apacemaker/defibrillator or other electrical stimulator system.Components of the system include a high-frequency pulse generator,sensors to monitor blood pressure or other pertinent physiologicalparameters, leads to apply electrical stimulation to baroreceptors,algorithms to determine the appropriate time to administer stimulation,and algorithms to manipulate data for display and patient management.

Various embodiments relate to a system that seeks to deliverelectrically mediated NS therapy, such as AHT therapy, to patients.Various embodiments combine a “stand-alone” pulse generator with aminimally invasive, unipolar lead that directly stimulates baroreceptorsin the vicinity of the heart, such as in the pulmonary artery. Thisembodiment is such that general medical practitioners lacking the skillsof specialist can implant it. Various embodiments incorporate a simpleimplanted system that can sense parameters indicative of blood pressure.This system adjusts the therapeutic output (waveform amplitude,frequency, etc.) so as to maintain a desired quality of life. In variousembodiments, an implanted system includes a pulse generating device andlead system, the stimulating electrode of which is positioned nearendocardial baroreceptor tissues using transvenous implant technique(s).Another embodiment includes a system that combines NS therapy withtraditional bradyarrhythmia, tachyarrhythmia, and/or congestive heartfailure (CHF) therapies. Some embodiments use an additional“baroreceptor lead” that emerges from the device header and is pacedfrom a modified traditional pulse generating system. In anotherembodiment, a traditional CRM lead is modified to incorporate proximalelectrodes that are naturally positioned near baroreceptor sites. Withthese leads, distal electrodes provide CRM therapy and proximateelectrodes stimulate baroreceptors.

A system according to these embodiments can be used to augment partiallysuccessful treatment strategies. As an example, undesired side effectsmay limit the use of some pharmaceutical agents. The combination of asystem according to these embodiments with reduced drug doses may beparticularly beneficial.

According to various embodiments, the lead(s) and the electrode(s) onthe leads are physically arranged with respect to the heart in a fashionthat enables the electrodes to properly transmit pulses and sensesignals from the heart, and with respect to baroreceptors to stimulatethe baroreflex. As there may be a number of leads and a number ofelectrodes per lead, the configuration can be programmed to use aparticular electrode or electrodes. According to various embodiments,the baroreflex is stimulated by stimulating afferent nerve trunks.

FIG. 12 illustrates a system 1220 including a programmer 1222, animplantable neural stimulator (NS) device 1237 and an implantablecardiac rhythm management (CRM) device 1238, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device 1237, such as an AHTdevice, and a CRM device 1238 or other cardiac stimulator. In variousembodiments, this communication allows one of the devices 1237 or 1238to deliver more appropriate therapy (i.e. more appropriate NS therapy orCRM therapy) based on data received from the other device. Someembodiments provide on-demand communications. In various embodiments,this communication allows each of the devices 1237 and 1238 to delivermore appropriate therapy (i.e. more appropriate NS therapy and CRMtherapy) based on data received from the other device. The illustratedNS device 1237 and the CRM device 1238 are capable of wirelesslycommunicating with each other, and the programmer is capable ofwirelessly communicating with at least one of the NS and the CRM devices1237 and 1238. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.

In some embodiments, the NS device 1237 stimulates the baroreflex toprovide NS therapy, and senses ANS activity directly or using surrogateparameters, such as respiration and blood pressure, indicative of ANSactivity. The CRM device 1238 includes cardiac stimulation capabilities,such as pacing and defibrillating capabilities. Rather than providingwireless communication between the NS and CRM devices 1237 and 1238,various embodiments provide a communication cable or wire, such as anintravenously-fed lead, for use to communicate between the NS device1237 and the CRM device 1238.

FIG. 13 illustrates an implantable neural stimulator (NS) device 1337such as shown at 1237 in the system of FIG. 12, according to variousembodiments of the present subject matter. FIG. 14 illustrates animplantable cardiac rhythm management (CRM) device 1438 such as shown at1238 in the system of FIG. 12, according to various embodiments of thepresent subject matter. Functions of the components for the NS device1337 were previously discussed with respect to FIGS. 9 and 11 (the NScomponent 1137), and functions of the components for the CRM device 1238were previously discussed with respect to FIG. 11 (the CRM component1138). In the interest of brevity, these discussions with respect to theNS and CRM functions are not repeated here. Various embodiments of theNS and CRM devices include wireless transceivers 1325 and 1425,respectively, to wirelessly communicate with each other. Variousembodiments of the NS and CRM devices include a telemetry coil orultrasonic transducer to wirelessly communicate with each other.

According to various embodiments, for example, the NS device is equippedwith a telemetry coil, allowing data to be exchanged between it and theCRM device, allowing the NS device to modify therapy based onelectrophysiological parameters such as heart rate, minute ventilation,atrial activation, ventricular activation, and cardiac events. Inaddition, the CRM device modifies therapy based on data received fromthe NS device, such as mean arterial pressure, systolic and diastolicpressure, and baroreceptors stimulation rate.

Some NS device embodiments are able to be implanted in patients withexisting CRM devices, such that the functionality of the NS device isenhanced by receiving physiological data that is acquired by the CRMdevice. The functionality of two or more implanted devices is enhancedby providing communication capabilities between or among the implanteddevices. In various embodiments, the functionality is further enhancedby designing the devices to wirelessly communicate with each other.

FIG. 15 illustrates a programmer 1522, such as the programmer 822 and1222 illustrated in the systems of FIGS. 8 and 12, or other externaldevice to communicate with the implantable medical device(s) 1237 and/or1238, according to various embodiments of the present subject matter. Anexample of another external device includes Personal Digital Assistants(PDAs) or personal laptop and desktop computers in an Advanced PatientManagement (APM) system. The illustrated device 1522 includes controllercircuitry 1545 and a memory 1546. The controller circuitry 1545 iscapable of being implemented using hardware, software, and combinationsof hardware and software. For example, according to various embodiments,the controller circuitry 1545 includes a processor to performinstructions embedded in the memory 1546 to perform a number offunctions, including communicating data and/or programming instructionsto the implantable devices. The illustrated device 1522 further includesa transceiver 1547 and associated circuitry for use to communicate withan implantable device. Various embodiments have wireless communicationcapabilities. For example, various embodiments of the transceiver 1547and associated circuitry include a telemetry coil for use to wirelesslycommunicate with an implantable device. The illustrated device 1522further includes a display 1548, input/output (I/O) devices 1549 such asa keyboard or mouse/pointer, and a communications interface 1550 for useto communicate with other devices, such as over a communication network.

Programmed Therapy Applications

NS and/or CRM functions of a system, whether implemented in two separateand distinct implantable devices or integrated as components into oneimplantable device, includes processes for performing NS and/or CRMtherapy or portions of the therapy. In some embodiments, the NS therapyprovides AHT therapy. These processes can be performed by a processorexecuting computer-readable instructions embedded in memory, forexample. These therapies include a number of applications, which havevarious processes and functions, some of which are identified anddiscussed below. The processes and functions of these therapies are notnecessarily mutually exclusive, as some embodiments of the presentsubject matter include combinations of two or more of thebelow-identified processes and functions.

Accounting for Neural Stimulation to Accurately Sense Signals

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from an neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter. Neural stimulation isaccounted for to improve the ability to sense signals, and thus reduceor eliminate false positives associated with detecting a cardiac event.The NS device includes an AHT device in some embodiments. For example,the NS device communicates with and prevents or otherwise compensatesfor baroreflex stimulation such that the CRM device does notunintentionally react to the baroreflex stimulation, according to someembodiments. Some embodiments automatically synchronize the baroreflexstimulation with an appropriate refraction in the heart. For example,some systems automatically synchronize stimulation of baroreceptors inor around the pulmonary artery with atrial activation. Thus, thefunctions of the CRM device are not adversely affected by detectingfar-field noise generated by the baroreflex stimulation, even when thebaroreflex stimulations are generated near the heart and the CRM sensorsthat detect the cardiac electrical activation.

FIG. 16A generally illustrates a system 1654 that includes NS functions1651 (such as may be performed by a NS device or a NS component in anintegrated NS/CRM device), CRM functions 1652 (such as may be performedby a CRM device or a CRM component in an integrated NS/CRM device) andcapabilities to communicate 1653 between the NS and CRM functions. Theillustrated communication is bidirectional wireless communication.However, the present subject matter also contemplates unidirectionalcommunication, and further contemplates wired communication.Additionally, the present subject matter contemplates that the NS andCRM functions 1651 and 1652 can be integrated into a single implantabledevice such that the communication signal is sent and received in thedevice, or in separate implantable devices. Although baroreflexstimulation as part of neural stimulation is specifically discussed,this aspect of the present subject matter is also applicable to prevent,or account or other wise compensate for, unintentional interferencedetectable by a sensor and generated from other electrical stimulators.

FIG. 16B illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. FIG. 16B illustrates a process where the NS device orcomponent 1651 sends an alert or otherwise informs the CRM device orcomponent when baroreceptors are being electrically stimulated. In theillustrated embodiment, the NS device/component determines at 1655 ifelectrical stimulation, such as baroreflex stimulation, is to beapplied. When electrical stimulation is to be applied, the NS device orcomponent 1651 sends at 1656 an alert 1657 or otherwise informs the CRMdevice or component 1652 of the electrical stimulation. At 1658, theelectrical stimulation is applied by the NS device/component. At 1659CRM therapy, including sensing, is performed. At 1660, the CRMdevice/component determines whether an alert 1657 has been received fromthe NS device/component. If an alert has been received, an eventdetection algorithm is modified at 1661 to raise a detection threshold,provide a blackout or blanking window, or otherwise prevent theelectrical stimulation in the NS device or component from beingmisinterpreted as an event by the CRM device/component.

FIG. 16C illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. The CRM device/component 1652 determines a refractoryperiod for the heart at 1662. At 1663, if a refractory period isoccurring or is expected to occur in a predictable amount of time, anenable 1664 corresponding to the refractory is provided to the NSdevice/component 1651. The AHT device/component 1651 determines ifelectrical stimulation is desired at 1665. When desired, the AHTdevice/component applies electrical stimulation during a refractoryperiod at 1666, as controlled by the enable signal 1664. FIG. 16Dillustrates a refractory period at 1667 in a heart and a baroreflexstimulation 1668, and further illustrates that baroreflex stimulation isapplied during the refractory period.

A refractory period includes both absolute and relative refractoryperiods. Cardiac tissue is not capable of being stimulated during theabsolute refractory period. The required stimulation threshold during anabsolute refractory period is basically infinite. The relativerefractory period occurs after the absolute refractory period. Duringthe relative refractory period, as the cardiac tissue begins torepolarize, the stimulation threshold is initially very high and dropsto a normal stimulation threshold by the end of the relative refractoryperiod. Thus, according to various embodiments, a neural stimulatorapplies neural stimulation during either the absolute refractory periodor during a portion of the relative refractory period corresponding asufficiently high stimulation threshold to prevent the neuralstimulation from capturing cardiac tissue.

Various embodiments of the present subject matter relate to a method ofsensing atrial activation and confining pulmonary artery stimulation tothe atrial refractory period, preventing unintentional stimulation ofnearby atrial tissue. An implantable baroreceptor stimulation devicemonitors atrial activation with an atrial sensing lead. A lead in thepulmonary artery stimulates baroreceptors in the vessel wall. However,instead of stimulating these baroreceptors continuously, the stimulationof baroreceptors in the pulmonary artery occurs during the atrialrefractory period to avoid capturing nearby atrial myocardium,maintaining the intrinsic atrial rate and activation. Variousembodiments of the present subject matter combine an implantable devicefor stimulating baroreceptors in the wall of the pulmonary artery withthe capability for atrial sensing. Various embodiments stimulatebaroreceptors in the cardiac fat pads, in the heart chambers, and/orafferent nerves.

FIG. 17 illustrates a system 1769 to modulate baroreflex stimulation,according to various embodiments of the present subject matter. Theillustrated system 1769 includes a baroreflex stimulator 1751, such asstimulator to stimulate baroreceptors in and around the pulmonaryartery. The baroreflex stimulator can be included in a stand-alone NSdevice or as a NS component in an integrated NS/CRM device, for example.The illustrated stimulator 1751 includes a modulator 1769 for use toselectively increase and decrease the applied baroreflex stimulation.According to various embodiments, the modulator 1769 includes any one ofthe following modules: a module 1770 to change the amplitude of thestimulation pulse; a module 1771 to change the frequency of thestimulation pulse; and a module 1772 to change the burst frequency ofthe stimulation pulse. The burst frequency can also be referred to as aduty cycle. According to various embodiments, the modulator 1769includes functions for the various combinations of two or more of themodules 1770, 1771 and 1772. Additionally, a stimulator can include awaveform generator capable of providing different waveforms in responseto a control signal.

Various embodiments of the system include any one or any combination ofa cardiac activity monitor 1773, an adverse event detector 1774, arespiration monitor 1775, and a circadian rhythm template 1776 which arecapable of controlling the modulator 1769 of the stimulator 1759 toappropriately apply a desired level of baroreflex stimulation. Each ofthese 1773, 1774, 1775, and 1776 are associated with a method tomodulate a baroreflex signal. According to various embodiments, thesystem includes means to modulate a baroreflex signal based on thefollowing parameters or parameter combinations: cardiac activity (1773);an adverse event (1774); respiration (1775); circadian rhythm (1776);cardiac activity (1773) and an adverse event (1774); cardiac activity(1773) and respiration (1775); cardiac activity (1773) and circadianrhythm (1776); an adverse event (1774) and respiration (1775); anadverse event (1774) and circadian rhythm (1776); respiration (1775) andcircadian rhythm (1776); cardiac activity (1773), an adverse event(1774), and respiration (1775); cardiac activity (1773), an adverseevent (1774), and circadian rhythm (1776); cardiac activity (1773),respiration (1775), and circadian rhythm (1776); an adverse event(1774), respiration (1775) and circadian rhythm (1776); and cardiacactivity (1773), an adverse event (1774), respiration (1775) andcircadian rhythm (1776).

The stimulation can be applied to an afferent nerve trunk such as thevagal nerve using a cuff electrode or an intravascularly-fed leadpositioned proximate to the nerve trunk. The stimulation can be appliedto baroreceptor sites such are located in the pulmonary artery, aorticarch, and carotid sinus, for example, using intravenously-fed leads. Thestimulation can be applied to baroreceptor sites located in cardiac fatpads using intravenously-fed leads or by screwing electrodes into thefat pads. Embodiments of the cardiac activity detector 1774, forexample, include any one or any combination of a heart rate monitor1777, a minute ventilation monitor 1778, and an acceleration monitor1779. The respiration monitor 1775 functions as a surrogate formonitoring blood pressure. Embodiments of the respiration monitor 1775include any one or any combination of a tidal volume monitor 1780 and aminute ventilation module 1781. Embodiments of the circadian rhythmtemplate 1776 include any one or combination of a custom generatedtemplate 1782 and a preprogrammed template 1783. These embodiments arediscussed in more detail below with respect to FIGS. 18A-18C, 19A-19B,20A-20B, 21A-21E, 22 and 23A-23C.

Various embodiments use the circadian rhythm template to provide AHTtherapy. Various embodiments use the circadian rhythm template toprovide apnea therapy.

Modulation of Baroreflex Stimulation Based on Systolic Intervals

Activation of the sympathetic or parasympathetic nervous systems isknown to alter certain systolic intervals, primarily the pre-ejectionperiod (PEP), the time interval between sensed electrical activitywithin the ventricle (e.g. sensing of the “R” wave) and the onset ofventricular ejection of blood. The PEP may be measured from the sensedelectrical event to the beginning of pressure increase in the pulmonaryartery, using a pulmonary arterial pressure sensor, or may be measuredto the beginning of an increase in intracardiac impedance, accompanyinga decrease in ventricular volume during ejection, using electrodespositioned in the right or spanning the left ventricle. At rest, asdetermined by heart rate or body activity measured with an accelerometerfor example, neural stimulation is modulated to maintain PEP in apre-programmed range. A sudden decrease in PEP indicates an increase insympathetic tone associated with exercise or emotional stress. Thiscondition may be used to decrease neural stimulation permittingincreases in heart rate and contractility necessary to meet metabolicdemand. In like manner, a subsequent dramatic lengthening of PEP marksthe end of increased metabolic demand. At this time control of bloodpressure with neural stimulation could recommence.

Modulation of Baroreflex Stimulation Based on Cardiac Activity

The present subject matter describes a method of automaticallymodulating baroreceptor stimulation based on cardiac activity, such ascan be determined by the heart rate, minute ventilation, accelerationand combinations thereof. The functionality of a device for electricallystimulating baroreceptors is enhanced by applying at least a relativelyhigh baropacing rate during rest when metabolic demand is relativelylow, and progressively less baropacing during physical exertion asmetabolic demand increases. Indices of cardiac activity are used toautomatically modulate the electrical stimulation of baroreceptors,allowing an implantable anti-hypertension device to respond to changesin metabolic demand. According to various embodiments, a CRM device,such as a pacemaker, AICD or CRT devices, also has a baroreceptorstimulation lead. The device monitors cardiac activity through existingmethods using, for example, a blended sensor. A blended sensor includestwo sensors to measure parameters such as acceleration and minuteventilation. The output of the blended sensor represents a compositeparameter. Various NS and AHT therapies use composite parameters derivedfrom two or more sensed parameters as discussed within this disclosure.At rest (lower cardiac activity) the device stimulates baroreceptors ata higher rate, reducing blood pressure and controlling hypertension. Ascardiac activity increases, the device responds by temporarily reducingbaroreceptor stimulation. This results in a temporary increase in bloodpressure and cardiac output, allowing the body to respond to increasedmetabolic demand. For example, some embodiments provide baroreflexstimulation during rest and withdraw baroreflex stimulation duringexercise to match normal blood pressure response to exercise. A pressuretransducer can be used to determine activity. Furthermore, activity canbe sensed using sensors that are or have been used to drive rateadaptive pacing. Examples of such sensors include sensor to detect bodymovement, heart rate, QT interval, respiration rate, transthoracicimpedance, tidal volume, minute ventilation, body posture,electroencephalogram (EEG), electrocardiogram (ECG), electrooculogram(EOG), electromyogram (EMG), muscle tone, body temperature, pulseoximetry, time of day and pre-ejection interval from intracardiacimpedance.

Various embodiments of the cardiac activity monitor includes a sensor todetect at least one pressure parameter such as a mean arterialparameter, a pulse pressure determined by the difference between thesystolic and diastolic pressures, end systolic pressure (pressure at theend of the systole), and end diastolic pressure (pressure at the end ofthe diastole). Various embodiments of the cardiac activity monitorinclude a stroke volume monitor. Heart rate and pressure can be used toderive stroke volume. Various embodiments of the cardiac activitymonitor use at least one electrogram measurement to determine cardiacactivity. Examples of such electrogram measurements include the R-Rinterval, the P-R interval, and the QT interval. Various embodiments ofthe cardiac activity monitor use at least one electrocardiogram (ECG)measurement to determine cardiac activity.

FIGS. 18A-18C illustrate methods for modulating baroreceptor stimulationbased on a cardiac activity parameter, according to various embodimentsof the present subject matter. The cardiac activity can be determined bya CRM device, an NS device, or an implantable device with NS/CRMcapabilities. A first process 1884A for modulating baroreceptorstimulation based on cardiac activity is illustrated in FIG. 18A. At1885A the activity level is determined. According to variousembodiments, the determination of activity level is based on heart rate,minute ventilation, acceleration or any combination of heart rate,minute ventilation, acceleration. In the illustrated process, theactivity level has two defined binary levels (e.g. HI and LO). In someembodiments, the LO level includes no stimulation. It is determinedwhether the activity level is HI or LO. At 1886A, the baroreceptorstimulation level is set based on the determined activity level. A LOstimulation level is set if the activity level is determined to be HI,and a HI stimulation level is set if the activity level is determined tobe LO.

A second process 1884B for modulating baroreceptor stimulation based oncardiac activity is illustrated in FIG. 18B. At 1885B the activity levelis determined. According to various embodiments, the determination ofactivity level is based on heart rate, minute ventilation, accelerationor any combination of heart rate, minute ventilation, acceleration. Inthe illustrated process, the activity level has more than two definedlevels or n defined levels. It is determined whether the activity levelis level 1, level 2 . . . or level n. The activity level labelscorrespond to an increasing activity. At 1886B, the baroreceptorstimulation level is set based on the determined activity level.Available stimulation levels include level n . . . level 2 and level 1,where the stimulation level labels correspond to increasing stimulation.According to various embodiments, the selected baroreceptor stimulationlevel is inversely related to the determined activity level. Forexample, if it is determined that the cardiac activity level is at thehighest level n, then the stimulation level is set to the lowest leveln. If it determined that the stimulation level is at the first or secondto the lowest level, level 1 or level 2 respectively, then thestimulation level is set to the first or second to the highest level,level 1 or level 2 respectively.

Another process 1884C for modulating baroreceptor stimulation based oncardiac activity is illustrated in FIG. 18C. At 1887, an acquiredcardiac activity parameter is compared to a target activity parameter.If the acquired cardiac activity is lower than the target activityparameter, baroreceptor stimulation is increased at 1888. If theacquired cardiac activity is higher than the target activity parameter,baroreceptor stimulation is decreased at 1889.

An aspect of the present subject matter relates to a method ofautomatically modulating the intensity of baroreceptor stimulation basedon respiration, as determined by tidal volume or minute ventilation.Instead of applying continuous baroreceptor stimulation, the NS devicemonitors the level of hypertension and delivers an appropriate level oftherapy, using respiration as a surrogate for blood pressure, allowingthe device to modulate the level of therapy. The present subject matteruses indices of respiration, such as impedance, to determined tidalvolume and minute ventilation and to automatically modulate baroreceptorstimulation. Thus, an implantable NS device is capable of determiningthe level of hypertension in the patient and respond by delivering anappropriate level of therapy. In various embodiments, an implantable NSdevice contains a sensor to measure tidal volume or minute ventilation.For example, various embodiments measure transthoracic impedance toobtain a rate of respiration. The device receives this data from a CRMdevice in some embodiments. The NS device periodically monitors theserespiration parameters. As respiration decreases or remains below aprogrammable target, the device stimulates baroreceptors at an increasedrate, reducing blood pressure and controlling hypertension. As meanarterial pressure increases towards the target, the device responds byreducing baroreceptor stimulation. In this way, the AHT devicecontinuously delivers an appropriate level of therapy.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter. The respiration parameter can be determinedby a CRM device, an NS device, or an implantable device with NS/CRMcapabilities. One embodiment of a method for modulating baroreceptorstimulation based on a respiration parameter is illustrated at 1910A inFIG. 19A. The respiration level is determined at 1911, and thebaroreceptor stimulation level is set at 1912 based on the determinedrespiration level. According to various embodiments, the desiredbaropacing level is tuned at 1913. For example, one embodiment comparesan acquired parameter to a target parameter at 1914. The baropacing canbe increased at 1915 or decreased at 1916 based on the comparison of theacquired parameter to the target parameter.

One embodiment of a method for modulating baroreceptor stimulation basedon a respiration parameter is illustrated at 1910B in FIG. 19B. At 1916,a baroreflex event trigger occurs, which triggers an algorithm for abaroreflex stimulation process. At 1917, respiration is compared to atarget parameter. Baroreflex stimulation is increased at 1918 ifrespiration is below the target and is decreased at 1919 if respirationis above the target. According to various embodiments, the stimulationis not changed if the respiration falls within a blanking window.Various embodiments use memory to provide a hysteresis effect tostabilize the applied stimulation and the baroreflex response.Additionally, in various embodiments, the respiration target is modifiedduring the therapy based on various factors such as the time of day oractivity level. At 1920, it is determined whether to continue with thebaroreflex therapy algorithm based on, for example, sensed parameters orthe receipt of an event interrupt. If the baroreflex algorithm is tocontinue, then the process returns to 1917 where respiration is againcompared to a target parameter; else the baroreflex algorithm isdiscontinued at 1921.

Modulation of Baroreflex Stimulation Based on Adverse Event

Aspects of the present subject matter include a method of automaticallyincreasing baroreceptor stimulation upon detection of an adverse cardiacevent to increase vasodilatory response and potentially prevent orreduce myocardial ischemic damage. Various embodiments include afeedback mechanism in a cardiac rhythm management device (such as apacemaker, AICD or CRT device), which also has a stimulation lead forelectrically stimulating baroreceptors. The device monitors cardiacelectrical activity through existing methods. In the event of an adversecardiac event such as ventricular fibrillation (VF) and atrialfibrillation (AF), ventricular tachycardia (VT) and atrial tachycardia(AT) above a predefined rate, and dyspnea as detected by a minuteventilation sensor, angina, decompensation and ischemia, the deviceresponds by increasing baroreceptors stimulation to the maximallyallowable level. As a result, blood pressure is temporarily lowered,potentially preventing or reducing myocardial damage due to ischemia.The functionality of a device to treat hypertension can be expanded ifit can respond to adverse cardiac events by temporarily modulating theextent of baroreceptors stimulation. Event detection algorithmsautomatically modulate baroreceptors stimulation, allowing animplantable AHT device to respond to an adverse event by increasingbaroreceptors stimulation, potentially preventing or reducing myocardialischemic damage.

FIGS. 20A-20B illustrate methods for modulating baroreceptor stimulationbased on detection of an adverse event, according to various embodimentsof the present subject matter. The adverse event can be determined by aCRM device, an NS device, or an implantable device with NS/CRMcapabilities. FIG. 20A illustrates one embodiment for modulatingbaroreceptor stimulation based on detection of an adverse event. At2090A, it is determined whether an adverse event has been detected. Ifan adverse event has not been detected, normal baropacing (baropacingaccording to a normal routine) is performed at 2091A. If an adverseevent has been detected, enhanced baropacing is performed at 2092. Invarious embodiments, the maximum allowable baropacing is performed whenan adverse event is detected. Other baropacing procedures can beimplemented. For example, various embodiments normally apply baropacingstimulation and withholds baropacing therapy when an adverse event isdetected, and various embodiments normally withhold baropacing therapyand apply baropacing stimulation when an adverse event is detected. FIG.20B illustrate on embodiment for modulating baroreceptor stimulationbased on detection of an adverse event. At 2090B, it is determinedwhether an adverse event has been detected. If an adverse event has notbeen detected, normal baropacing (baropacing according to a normalroutine) is performed at 2091B. If an adverse event has been detected,the event is identified at 2093, and the appropriate baropacing for theidentified adverse event is applied at 2094. For example, proper bloodpressure treatment may be different for ventricular fibrillation thanfor ischemia. According to various embodiments, the desired baropacingis tuned for the identified event at 2095. For example, one embodimentcompares an acquired parameter to a target parameter at 2096. Thebaropacing can be increased at 2097 or decreased at 2098 based on thecomparison of the acquired parameter to the target parameter.

According to various embodiments, an adverse event includes detectableprecursors, such that therapy can be applied to prevent cardiacarrhythmia. In some embodiments, an adverse event includes both cardiacevents and non-cardiac events such as a stroke. Furthermore, someembodiments identify both arrhythmic and non-arrhythmic events asadverse events.

Modulation of Baroreflex Stimulation Based on Circadian Rhythm

An aspect of the present subject matter relates to a method forstimulating the baroreflex in hypertension patients so as to mimic thenatural fluctuation in blood pressure that occurs over a 24-hour period.Reflex reduction in hypertension is achieved during long-termbaroreceptor stimulation without altering the intrinsic fluctuation inarterial pressure. According to various embodiments, an implantabledevice is designed to stimulate baroreceptors in the carotid sinus,pulmonary artery, or aortic arch using short, high-frequency bursts(such as a square wave with a frequency within a range fromapproximately 20-150 Hz), for example. Some embodiments directlystimulate the carotid sinus nerve, aortic nerve or vagus nerve with acuff electrode. However, the bursts do not occur at a constant rate.Rather the stimulation frequency, amplitude, and/or burst frequencyrises and falls during the day mimicking the natural circadian rhythm.

Thus, various embodiments of a NS device accounts for naturalfluctuations in arterial pressure that occur in both normal andhypertensive individuals. Aside from activity-related changes in meanarterial pressure, subjects also exhibit a consistent fluctuation inpressure on a 24-hour cycle. A device which provides periodicbaroreceptor stimulation mimics the intrinsic circadian rhythm, allowingfor reflex inhibition of the systematic nervous system and reducedsystemic blood pressure without disturbing this rhythm. The presentsubject matter provides a pacing protocol which varies the baroreceptorstimulation frequency/amplitude in order to reduce mean arterialpressure without disturbing the intrinsic circadian rhythm.

FIGS. 21A-21E illustrate circadian rhythm. FIG. 21A illustrates thecircadian rhythm associated with mean arterial pressure for 24 hoursfrom noon to noon; FIG. 21B illustrates the circadian rhythm associatedwith heart rate for 24 hours from noon to noon; FIG. 21C illustrates thecircadian rhythm associated with percent change of stroke volume (SV %)for 24 hours from noon to noon; FIG. 21D illustrates the circadianrhythm associated with the percent change of cardiac output (CO) for 24hours from noon to noon; and FIG. 21E illustrates the circadian rhythmassociated with percent change of total peripheral resistance (TPR %),an index of vasodilation, for 24 hours from noon to noon. Variousembodiments graph absolute values, and various embodiments graph percentvalues. In these figures, the shaded portion represents night hours fromabout 10 PM to 7 AM, and thus represents rest or sleep times. Referringto FIGS. 21A and 21B, for example, it is evident that both the meanarterial pressure and the heart rate are lowered during periods of rest.A higher blood pressure and heart rate can adversely affect rest.Additionally, a lower blood pressure and heart rate during the day canadversely affect a person's level of energy.

Various embodiments of the present subject matter modulate baroreflexstimulation using a pre-programmed template intended to match thecircadian rhythm for a number of subjects. Various embodiments of thepresent subject matter generate a template customized to match asubject.

FIG. 22 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter, using a customized circadian rhythm template.The illustrated method 2222 senses and records parameters related tohypertension at 2223. Examples of such parameters include heart rate andmean arterial pressure. At 2224, a circadian rhythm template isgenerated based on these recorded parameters. At 2225, the baroreflexstimulation is modulated using the circadian rhythm template generatedin 2224.

Modulation of Baroreflex Stimulation to Provide Desired Cardiac Output

An aspect of the present subject matter relates to an implantablemedical device that provides NS therapy to lower systemic blood pressureby stimulating the baroreflex, and further provides cardiac pacingtherapy using a cardiac pacing lead for rate control. Baroreflexstimulation and cardiac pacing occurs in tandem, allowing blood pressureto be lowered without sacrificing cardiac output.

According to various embodiments, a baroreflex stimulator communicateswith a separate implantable CRM device, and uses the existing pacinglead. In various embodiments, baroreflex stimulation occurs throughbaroreceptors in the pulmonary artery, carotid sinus, or aortic archwith an electrode placed in or adjacent to the vessel wall. In variousembodiments, afferent nerves such as the aortic nerve, carotid sinusnerve, or vagus nerve are stimulated directly with a cuff electrode.

Baroreflex stimulation quickly results in vasodilation, and decreasessystemic blood pressure. To compensate for the concurrent decrease incardiac output, the pacing rate is increased during baroreflexstimulation. The present subject matter allows blood pressure to begradually lowered through baroreflex stimulation while avoiding the dropin cardiac output that otherwise accompanies such stimulation bycombining baroreflex stimulation with cardiac pacing, allowing animplantable device to maintain cardiac output during blood pressurecontrol.

FIG. 23A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter. FIG. 23A illustrates one embodiment formodulating baroreceptor stimulation based on a cardiac output parameter.In the illustrated process 2326A, it is determined whether baroreflexstimulation is being applied at 2327. If baroreflex stimulation is notbeing applied, the present subject matter implements the appropriatepacing therapy, if any, at 2328 with the appropriate pacing rate. Ifbaroreflex stimulation is not being applied, the present subject matterimplements a pacing therapy at 2329 with a higher pacing rate tomaintain cardiac output.

FIG. 23B illustrates one embodiment for modulating baroreceptorstimulation based on a cardiac output parameter. In the illustratedprocess 2326B, baroreflex stimulation is applied at 2330, and it isdetermined whether the cardiac output is adequate at 2331. Upondetermining that the cardiac output is not adequate, the pacing rate isincreased at 2332 to maintain adequate cardiac output.

According to various embodiments, an existing pacing rate is increasedby a predetermined factor during baroreflex stimulation to maintaincardiac output. In various embodiments, a pacing rate is initiatedduring baroreflex stimulation to maintain cardiac output. Modulatingbaroreflex stimulation to provide desired cardiac output can beimplemented with atrial and ventricular rate control, AV delay control,resynchronization, and multisite stimulation. Alternatively, the strokevolume may be monitored by right ventricular impedance using electrodeswithin the right ventricular cavity or by left ventricular impedanceusing electrodes within or spanning the left ventricular cavity, and thepacing rate may be increased using application of neural stimulation tomaintain a fixed cardiac output.

Modulation of Baroreflex Stimulation To Remodel Stiffening Process

Aspects of the present subject matter involve a method for baroreflexstimulation, used by an implantable NS device, to lower systemic bloodpressure in patients with refractory hypertension. A baroreflexstimulation algorithm gradually increases baroreflex stimulation toslowly adjust blood pressure towards a programmable target. Thisalgorithm prevents the central nervous system from adapting to aconstant increased level of baroreflex stimulation, which ordinarilyattenuates the pressure-lowering effect. In addition, the gradual natureof the blood pressure change allows the patient to better tolerate thetherapy, without abrupt changes in systemic blood pressure and cardiacoutput.

The present subject matter provides a specific algorithm or processdesigned to prevent central nervous system adaptation to increasedbaroreflex stimulation, to slowly decrease blood pressure levels withtime to enable for the reversion of the arterial stiffening processtriggered by the previous hypertensive state present in the patient, andto prevent cardiac output decreases during baroreceptor stimulation. Itis expected that, with time, the arterial system reverse remodels thestiffening process that was started by the previously presenthypertension. The slow and progressive lowering of the mean/median bloodpressure enables the slow reversion of this stiffening process throughthe reverse remodeling. Blood pressure is reduced without compromisingcardiac output in the process, thus avoiding undesired patient symptoms.

In various embodiments, the device stimulates baroreceptors in thepulmonary artery, carotid sinus, or aortic arch with an electrode placedin or adjacent to the vessel wall. In various embodiments afferentnerves such as the aortic nerve, carotid sinus nerve, or vagus nerve arestimulated directly with a cuff electrode. The stimulated baroreflexquickly results in vasodilation, and a decrease in systemic bloodpressure. However, rather than stimulating the baroreflex at a constant,elevated level, the device of the present subject matter initiallystimulates at a slightly increased level, and then gradually increasesthe stimulation over a period of weeks or months, for example. The rateof change is determined by the device based on current and targetarterial pressure. In various embodiments, the system determines therate of change based on direct or indirect measurements of cardiacoutput, to ensure that the decrease in pressure is not occurring at theexpense of a decreased cardiac output. In various embodiments, the rateof baroreflex stimulation is not constant but has a white noise typedistribution to more closely mimic the nerve traffic distribution. Bymimicking the nerve traffic distribution, it is expected that thebaroreflex is more responsive to the stimulation, thus lowering thethreshold for stimulating the baroreflex.

FIG. 24 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter. A baroreflex event trigger occurs at 2433. Thistrigger includes any event which initiates baroreflex stimulation,including the activation of an AHT device. At 2434, an algorithm isimplemented to increase baroreflex stimulation by a predetermined rateof change to gradually lower the blood pressure to a target pressure inorder to reverse remodel the stiffening process. At 2435, it isdetermined whether to continue with the baroreflex stimulationalgorithm. The algorithm may be discontinued at 2436 based on an eventinterrupt, sensed parameters, and/or reaching the target blood pressure,for example. At 2437, it is determined whether the cardiac output isacceptable. If the cardiac output in not acceptable, at 2438 the rate ofchange for the baroreflex stimulate is modified based on the cardiacoutput.

Baroreflex Stimulation to Treat Myocardial Infarction

Following a myocardial infarction, myocytes in the infarcted region dieand are replaced by scar tissue, which has different mechanical andelastic properties from functional myocardium. Over time, this infarctedarea can thin and expand, causing a redistribution of myocardialstresses over the entire heart. Eventually, this process leads toimpaired mechanical function in the highly stressed regions and heartfailure. The highly stressed regions are referred to as being heavily“loaded” and a reduction in stress is termed “unloading.” A device totreat acute myocardial infarction to prevent or reduce myocardial damageis desirable.

An aspect of the present subject matter relates to an implantable devicethat monitors cardiac electrical activity. Upon detection of amyocardial infarction, the device electrically stimulates thebaroreflex, by stimulating baroreceptors in or adjacent to the vesselwalls and/or by directly stimulating pressure-sensitive nerves.Increased baroreflex stimulation compensates for reduced baroreflexsensitivity, and improves the clinical outcome in patients following amyocardial infarction. An implantable device (for example, a CRM device)monitors cardiac electrical activity. Upon detection of a myocardialinfarction, the device stimulates the baroreflex. Some embodiments ofthe device stimulate baroreceptors in the pulmonary artery, carotidsinus, or aortic arch with an electrode placed in or adjacent to thevessel wall. In various embodiments, afferent nerves such as the aorticnerve are stimulated directly with a cuff electrode, or with a leadintravenously placed near the afferent nerve. Afferent nerves such asthe carotid sinus nerve or vagus nerve are stimulated directly with acuff electrode, or with a lead intravenously placed near the afferentnerve. In various embodiments, a cardiac fat pad is stimulated using anelectrode screwed into the fat pad, or a lead intravenously fed into avessel or chamber proximate to the fat pad.

Baroreflex stimulation quickly results in vasodilation, and a decreasein systemic blood pressure. This compensates for reduced baroreflexsensitivity and reduces myocardial infarction. According to variousembodiments, systemic blood pressure, or a surrogate parameter, aremonitored during baroreflex stimulation to insure that an appropriatelevel of stimulation is delivered. Some aspects and embodiments of thepresent subject matter provides baroreflex stimulation to preventischemic damage following myocardial infarction.

FIGS. 25A-25B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter. FIG. 25A illustrates a system that includes a myocardialinfarction detector 2539 and a baroreflex or baroreceptor stimulator2540. A myocardial infarction can be detected using anelectrocardiogram, for example. For example, a template can be comparedto the electrocardiogram to determine a myocardial infarction. Anotherexample detects changes in the ST segment elevation to detect myocardialinfarction. In various embodiments, the detector 2539 and stimulator2540 are integrated into a single implantable device such as in an AHTdevice or a CRM device, for example. In various embodiments, thedetector 2539 and stimulator 2540 are implemented in separateimplantable devices that are adapted to communicate with each other.

FIG. 25B illustrates a method to detect myocardial infarction andperform baropacing in response to the detected myocardial infarction,according to various embodiments of the present subject matter. At 2541,it is determined whether a myocardial infarction has occurred. Upondetermining that a myocardial infarction has occurred, the baroreflex isstimulated at 2542. For example, in various embodiments, thebaroreceptors in and around the pulmonary artery are stimulated using alead fed through the right atrium and the pulmonary valve and into thepulmonary artery. Other embodiments stimulate other baroreceptor sitesand pressure sensitive nerves. Some embodiments monitor the systemicblood pressure or a surrogate parameter at 2543, and determines at 2544if the stimulation should be adjusted based on this monitoring. If thestimulation is to be adjusted, the baroreflex stimulation is modulatedat 2545. Examples of modulation include changing the amplitude,frequency, burst frequency and/or waveform of the stimulation.

Neural stimulation, such as baroreflex stimulation, can be used tounload after a myocardial infarction. Various embodiments use an acutemyocardial infraction detection sensor, such as an ischemia sensor,within a feedback control system of an NS device. However, a myocardialinfraction detection sensor is not required. For example, a stimulationlead can be implanted after a myocardial infarction. In variousembodiments, the stimulation lead is implanted through the right atriumand into the pulmonary artery to stimulate baroreceptors in and aroundthe pulmonary artery. Various embodiments implant stimulation cuffs orleads to stimulate afferent nerves, electrode screws or leads tostimulate cardiac fat pads, and leads to stimulate other baroreceptorsas provided elsewhere in this disclosure.

Electrical pre-excitation of a heavily loaded region will reduce loadingon this region. This pre-excitation may significantly reduce cardiacoutput resulting in sympathetic activation and an increase in globalstress, ultimately leading to deleterious remodeling of the heart. Thisprocess may be circumvented by increased neural stimulation to reducethe impact of this reflex. Thus, activation of the parasympatheticnervous system during pre-excitation may prevent the undesirableside-effects of unloading by electrical pre-excitation.

FIG. 26 is a block diagram illustrating an embodiment of a circuit of aneural stimulation system 2646. System 2646 includes a reference signalsensor 2647, a data sensor 2648 adapted to sense a physiologic responseto the neural stimulation, a stimulation electrode/transducer 2649, anda neural stimulation circuit 2650. Reference signal sensor 2647 senses areference signal indicative of cardiac cycles each including apredetermined type timing reference event. In one embodiment, referencesignal sensor 2647 is an implantable reference signal sensor. The timingreference event is a recurring feature of the cardiac cycle that ischosen to be a timing reference to which the neural stimulation issynchronized. In an embodiment, reference signal sensor 2647 includes anelectrode in or near the heart, such as may be incorporated in anintracardiac lead. In one embodiment, reference signal sensor 2647 isconfigured for extracardiac and extravascular placement, i.e., placementexternal to the heart and blood vessels. Examples of reference signalsensor 2647 include a set of electrodes for sensing a subcutaneous ECGsignal, an acoustic sensor for sensing an acoustic signal indicative ofheart sounds, and a hemodynamic sensor for sensing a hemodynamic signalindicative of hemodynamic performance. In one embodiment, an implantablemedical device has an implantable housing that contains both a referencesignal sensor 2647 and neural stimulation circuit 2650. In anembodiment, reference signal sensor 2647 is incorporated onto thehousing of an implantable medical device. In another embodiment,reference signal sensor 2647 is electrically connected to an implantablemedical device through one or more leads. In another embodiment,reference signal sensor 2647 is communicatively coupled to animplantable medical device via an intra-body telemetry link.

Neural stimulation circuit 2650 includes a stimulation output circuit2651, a reference event detection circuit 2652, a feedback detectioncircuit 2653, and a stimulation control circuit 2654. Reference eventdetection circuit 2652 receives the reference signal from referencesignal sensor 2647 and detects the timing reference event from thereference signal. Stimulation control circuit 2654 controls the deliveryof the neural stimulation pulses and includes a synchronization circuitor module 2655 and a therapy titration adjustment circuit or module2656. Synchronization module 2655 receives a signal indicative of thedetection of each timing reference event and synchronizes the deliveryof the neural stimulation pulses to the detected timing reference event.Stimulation output circuit 2651 delivers neural stimulation pulses uponreceiving a pulse delivery signal from stimulation control circuit 2654.Data sensor 2648 provides signals indicative of a physiological responseto the applied neural stimulation. A feedback detection circuit 2653receives the signal indicative of the response and processes the signalto provide a neural stimulation feedback signal. In various embodiments,the response includes a cardiac activity such as heart rate, HRV, HRT,PR interval, T-wave velocity, or action potential duration. In variousembodiments the response includes a non-cardiac response such asrespiration or blood pressure. In various embodiments, the responseincludes a QT interval or atrial/ventricular refractory periods. Thetherapy titration/adjustment module 2656 uses the feedback signal tomodulate or titrate the therapy generated by the stimulation outputcircuit 2651 to provide the desired physiologic response (e.g. cardiacresponse or non-cardiac response). Contextual sensor(s) or input(s) 2657are also illustrated connected to the feedback detection circuit 2653 toprovide a more complete picture of a patient's physiology. The feedbackdetection circuit can provide the neural stimulation feedback signalbased on the sensor 2648 and the contextual input(s) 2657. Thecontextual input(s) can be used to avoid incomplete data from affectingthe neural stimulation. Examples of contextual inputs include anactivity sensor, a posture sensor and a timer. Any one or combination oftwo or more contextual inputs can be used by the feedback detectioncircuit. For example, an elevated heart rate may be representative ofexercise rather than a reason for titrating the neural stimulationtherapy.

FIG. 27 illustrates an embodiment of a therapy titration module 2756such as is illustrated at 2656 in FIG. 26. According to variousembodiments, the stimulation control circuit is adapted to set or adjustany one or any combination of stimulation features 2758. Examples ofstimulation features include the amplitude, frequency, polarity and wavemorphology of the stimulation signal. Examples of wave morphologyinclude a square wave, triangle wave, sinusoidal wave, and waves withdesired harmonic components to mimic white noise such as is indicativeof naturally-occurring baroreflex stimulation. Some embodiments of thestimulation output circuit are adapted to generate a stimulation signalwith a predetermined amplitude, morphology, pulse width and polarity,and are further adapted to respond to a control signal from thecontroller to modify at least one of the amplitude, wave morphology,pulse width and polarity. Some embodiments of the neural stimulationcircuitry are adapted to generate a stimulation signal with apredetermined frequency, and are further adapted to respond to a controlsignal from the controller to modify the frequency of the stimulationsignal.

The therapy titration module 2756 can be programmed to changestimulation sites 2759, such as changing the stimulation electrodes usedfor a neural target or changing the neural targets for the neuralstimulation. For example, different electrodes of a multi-electrode cuffcan be used to stimulate a neural target. Examples of neural targetsinclude the right and left vagus nerves, cardiac branches of the vagusnerve, cardiac fats pads, baroreceptors, the carotid sinus, the carotidsinus nerve, and the aortic nerve. Autonomic neural targets can includeafferent pathways and efferent pathways and can include sympathetic andparasympathetic nerves. The stimulation can include stimulation tostimulate neural traffic or stimulation to inhibit neural traffic. Thus,stimulation to evoke a sympathetic response can involve sympatheticstimulation and/or parasympathetic inhibition; and stimulation to evokea parasympathetic response can involve parasympathetic stimulationand/or sympathetic inhibition.

The therapy titration module 2756 can be programmed to changestimulation vectors 2760. Vectors can include stimulation vectorsbetween electrodes, or stimulation vectors for transducers. For example,the stimulation vector between two electrodes can be reversed. Onepotential application for reversing stimulation vectors includeschanging from stimulating neural activity at the neural target toinhibiting neural activity at the neural target. More complicatedcombinations of electrodes can be used to provide more potentialstimulation vectors between or among electrodes. One potentialstimulation vector application involves selective neural stimulation(e.g. selective stimulation of the vagus nerve) or changing between aselective stimulation and a more general stimulation of a nerve trunk.

The therapy titration module 2756 can be programmed to control theneural stimulation according to stimulation instructions, such as astimulation routine or schedule 2761, stored in memory. Neuralstimulation can be delivered in a stimulation burst, which is a train ofstimulation pulses at a predetermined frequency. Stimulation bursts canbe characterized by burst durations and burst intervals. A burstduration is the length of time that a burst lasts. A burst interval canbe identified by the time between the start of successive bursts. Aprogrammed pattern of bursts can include any combination of burstdurations and burst intervals. A simple burst pattern with one burstduration and burst interval can continue periodically for a programmedperiod or can follow a more complicated schedule. The programmed patternof bursts can be more complicated, composed of multiple burst durationsand burst interval sequences. The programmed pattern of bursts can becharacterized by a duty cycle, which refers to a repeating cycle ofneural stimulation ON for a fixed time and neural stimulation OFF for afixed time. Duty cycle is specified by the ON time and the cycle time,and thus can have units of ON time/cycle time. According to someembodiments, the control circuit 2654 controls the neural stimulationgenerated by the stimulation circuitry by initiating each pulse of thestimulation signal. In some embodiments, the stimulation control circuitinitiates a stimulation signal pulse train, where the stimulation signalresponds to a command from the controller circuitry by generating atrain of pulses at a predetermined frequency and burst duration. Thepredetermined frequency and burst duration of the pulse train can beprogrammable. The pattern of pulses in the pulse train can be a simpleburst pattern with one burst duration and burst interval or can follow amore complicated burst pattern with multiple burst durations and burstintervals. In some embodiments, the stimulation control circuit controlsthe stimulation output circuit to initiate a neural stimulation sessionand to terminate the neural stimulation session. The burst duration ofthe neural stimulation session under the control of the control circuit2654 can be programmable. The controller may also terminate a neuralstimulation session in response to an interrupt signal, such as may begenerated by one or more sensed parameters or any other condition whereit is determined to be desirable to stop neural stimulation.

The illustrated device includes a programmed therapy schedule or routinestored in memory and further includes a clock or timer which can be usedto execute the programmable stimulation schedule. For example, aphysician can program a daily/weekly schedule of therapy based on thetime of day. A stimulation session can begin at a first programmed time,and can end at a second programmed time. Various embodiments initiateand/or terminate a stimulation session based on a signal triggered by auser. Various embodiments use sensed data to enable and/or disable astimulation session.

According to various embodiments, the stimulation schedule refers to thetime intervals or period when the neural stimulation therapy isdelivered. A schedule can be defined by a start time and an end time, ora start time and a duration. Various schedules deliver therapyperiodically. By way of example and not limitation, a device can beprogrammed with a therapy schedule to deliver therapy from midnight to 2AM every day, or to deliver therapy for one hour every six hours, or todeliver therapy for two hours per day, or according to a morecomplicated timetable. Various device embodiments apply the therapyaccording to the programmed schedule contingent on enabling conditions,such as sensed exercise periods, patient rest or sleep, low heart ratelevels, and the like. For example, the stimulation can be synchronizedto the cardiac cycle based on detected events that enable thestimulation. The therapy schedule can also specify how the stimulationis delivered.

FIG. 28 illustrates an implantable medical device (IMD), according tovarious embodiments of the present subject matter. The illustrated IMD2862 provides neural stimulation signals for delivery to predeterminedneural targets. The illustrated device includes controller circuitry2863 and memory 2864. The controller circuitry is capable of beingimplemented using hardware, software, and combinations of hardware andsoftware. For example, according to various embodiments, the controllercircuitry includes a processor to perform instructions embedded in thememory to perform functions associated with the neural stimulationtherapy. The illustrated device further includes a transceiver 2865 andassociated circuitry for use to communicate with a programmer or anotherexternal or internal device. Various embodiments have wirelesscommunication capabilities. For example, some transceiver embodimentsuse a telemetry coil to wirelessly communicate with a programmer oranother external or internal device.

The illustrated device further includes neural stimulation outputcircuitry 2866 and sensor circuitry 2867. According to some embodiments,one or more leads are able to be connected to the sensor circuitry andneural stimulation circuitry. Some embodiments use wireless connectionsbetween the sensor(s) and sensor circuitry, and some embodiments usewireless connections between the stimulator circuitry and electrodes.According to various embodiments, the neural stimulation circuitry isused to apply electrical stimulation pulses to desired neural targets,such as through one or more stimulation electrodes 2868 positioned atpredetermined location(s). Some embodiments use transducers to provideother types of energy, such as ultrasound, light or magnetic energy. Invarious embodiments, the sensor circuitry is used to detectphysiological responses. Examples of physiological responses includecardiac activity such as heart rate, HRV, PR interval, T-wave velocity,and action potential duration. Other examples of physiological responsesinclude hemodynamic responses such as blood pressure, and respiratoryresponses such as tidal volume and minute ventilation. The controllercircuitry can control the therapy provided by system using a therapyschedule and a therapy titration routine in memory 2864, or can comparea target range (or ranges) of the sensed physiological response(s)stored in the memory 2864 to the sensed physiological response(s) toappropriately adjust the intensity of the neural stimulation/inhibition.

Some embodiments are adapted to change a stimulation signal feature, theneural stimulation target and/or change the neural stimulation vector aspart of a neural stimulation titration routine. According to variousembodiments using neural stimulation, the stimulation output circuitry2866 is adapted to set or adjust any one or any combination ofstimulation features based on commands from the controller 2863.Examples of stimulation features include the amplitude, frequency,polarity and wave morphology of the stimulation signal. Examples of wavemorphology include a square wave, triangle wave, sinusoidal wave, andwaves with desired harmonic components to mimic white noise such as isindicative of naturally-occurring baroreflex stimulation. Someembodiments are adapted to generate a stimulation signal with apredetermined amplitude, morphology, pulse width and polarity, and arefurther adapted to respond to a control signal from the controller tomodify at least one of the amplitude, wave morphology, pulse width andpolarity. Some embodiments are adapted to generate a stimulation signalwith a predetermined frequency, and are further adapted to respond to acontrol signal from the controller to modify the frequency of thestimulation signal.

The controller 2863 can be programmed to control the neural stimulationdelivered by the stimulation output circuitry 2866 according tostimulation instructions, such as a stimulation schedule, stored in thememory 2864. Neural stimulation can be delivered in a stimulation burst,which is a train of stimulation pulses at a predetermined frequency.Stimulation bursts can be characterized by burst durations and burstintervals. A burst duration is the length of time that a burst lasts. Aburst interval can be identified by the time between the start ofsuccessive bursts. A programmed pattern of bursts can include anycombination of burst durations and burst intervals. A simple burstpattern with one burst duration and burst interval can continueperiodically for a programmed period or can follow a more complicatedschedule. The programmed pattern of bursts can be more complicated,composed of multiple burst durations and burst interval sequences. Theprogrammed pattern of bursts can be characterized by a duty cycle, whichrefers to a repeating cycle of neural stimulation ON for a fixed timeand neural stimulation OFF for a fixed time.

According to some embodiments, the controller 2863 controls the neuralstimulation generated by the stimulation circuitry by initiating eachpulse of the stimulation signal. In some embodiments, the controllercircuitry initiates a stimulation signal pulse train, where thestimulation signal responds to a command from the controller circuitryby generating a train of pulses at a predetermined frequency and burstduration. The predetermined frequency and burst duration of the pulsetrain can be programmable. The pattern of pulses in the pulse train canbe a simple burst pattern with one burst duration and burst interval orcan follow a more complicated burst pattern with multiple burstdurations and burst intervals. In some embodiments, the controller 2863controls the stimulator output circuitry 2866 to initiate a neuralstimulation session and to terminate the neural stimulation session. Theburst duration of the neural stimulation session under the control ofthe controller 2863 can be programmable. The controller may alsoterminate a neural stimulation session in response to an interruptsignal, such as may be generated by one or more sensed parameters or anyother condition where it is determined to be desirable to stop neuralstimulation.

The sensor circuitry is used to detect a physiological response. Thedetected response can be cardiac activity or surrogates of cardiacactivity such as blood pressure and respiration measurements. Examplesof cardiac activity include a P-wave and heart rate. The controller 2863compares the response to a target range stored in memory, and controlsthe neural stimulation based on the comparison in an attempt to keep theresponse within the target range. The target range can be programmable.

The illustrated device includes a clock or timer 2869 which can be usedto execute the programmable stimulation schedule. For example, aphysician can program a daily schedule of therapy based on the time ofday. The therapy can be delivered in synchrony with cardiac activity(synch routine in memory 2864) and with cardiac activity feedback(titrate/feedback routine in memory 2864). A stimulation session canbegin at a first programmed time, and can end at a second programmedtime. Various embodiments initiate and/or terminate a stimulationsession based on a signal triggered by a user. Various embodiments usesensed data to enable and/or disable a stimulation session.

The illustrated memory includes a schedule. According to variousembodiments, the schedule refers to the time intervals or period whenthe neural stimulation therapy is delivered. A schedule can be definedby a start time and an end time, or a start time and a duration. Variousschedules deliver therapy periodically. According to various examples, adevice can be programmed with a therapy schedule to deliver therapy frommidnight to 2 AM every day, or to deliver therapy for one hour every sixhours, or to delivery therapy for two hours per day, or according to amore complicated timetable. Various device embodiments apply the therapyaccording to the programmed schedule contingent on enabling conditions,such as poor glucose control, patient rest or sleep, low heart ratelevels, and the like. The illustrated memory includes a synchronizationroutine and a titration feedback routine, which are used by the controlto control the timing and adjustments of neural stimulation generated bythe neural stimulator output circuitry.

FIG. 29 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 2970 whichcommunicates with a memory 2971 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the figure are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 2972A-C and tip electrodes 2973A-C, sensing amplifiers2974A-C, pulse generators 2975A-C, and channel interfaces 2976A-C. Eachchannel thus includes a pacing channel made up of the pulse generatorconnected to the electrode and a sensing channel made up of the senseamplifier connected to the electrode. The channel interfaces communicatebidirectionally with the microprocessor, and each interface may includeanalog-to-digital converters for digitizing sensing signal inputs fromthe sensing amplifiers and registers that can be written to by themicroprocessor in order to output pacing pulses, change the pacing pulseamplitude, and adjust the gain and threshold values for the sensingamplifiers. The sensing circuitry of the pacemaker detects a chambersense, either an atrial sense or ventricular sense, when an electrogramsignal (i.e., a voltage sensed by an electrode representing cardiacelectrical activity) generated by a particular channel exceeds aspecified detection threshold. Pacing algorithms used in particularpacing modes employ such senses to trigger or inhibit pacing. Theintrinsic atrial and/or ventricular rates can be measured by measuringthe time intervals between atrial and ventricular senses, respectively,and used to detect atrial and ventricular tachyarrhythmias. The sensingof these channels can be used to detect cardiac activity for use insynchronizing neural stimulation and for use as feedback in titratingthe neural stimulation.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 2977 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 2978 or an electrode on another lead serving as aground electrode. A shock pulse generator 2979 is also interfaced to thecontroller for delivering a defibrillation shock via a pair of shockelectrodes 2980 and 2981 to the atria or ventricles upon detection of ashockable tachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic stimulationand/or sympathetic inhibition, where one channel includes a bipolar leadwith a first electrode 2982D and a second electrode 2983D, a pulsegenerator 2984D, and a channel interface 2985D, and the other channelincludes a bipolar lead with a first electrode 2982E and a secondelectrode 2983E, a pulse generator 2984E, and a channel interface 2985E.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Thepulse generator for each channel outputs a train of neural stimulationpulses which may be varied by the controller as to amplitude, frequency,duty-cycle, and the like. In this embodiment, each of the neuralstimulation channels uses a lead which can be intravascularly disposednear an appropriate neural target. Other types of leads and/orelectrodes may also be employed. A nerve cuff electrode may be used inplace of an intravascularly disposed electrode to provide neuralstimulation. In some embodiments, the leads of the neural stimulationelectrodes are replaced by wireless links.

The figure illustrates a telemetry interface 2986 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor is capable of performing neuralstimulation therapy routines and myocardial (CRM) stimulation routines.The neural stimulation routines can target nerves to affect cardiacactivity (e.g. heart rate and contractility). Examples of myocardialtherapy routines include bradycardia pacing therapies, anti-tachycardiashock therapies such as cardioversion or defibrillation therapies,anti-tachycardia pacing therapies (ATP), and cardiac resynchronizationtherapies (CRT).

FIG. 30 is a block diagram illustrating an embodiment of an externalsystem 3087. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system 3087 isa patient management system including an external device 3088, atelecommunication network 3089, and a remote device 3090. Externaldevice 3088 is placed within the vicinity of an IMD and includesexternal telemetry system 3091 to communicate with the IMD. Remotedevice(s) 3090 is in one or more remote locations and communicates withexternal device 3088 through network 3089, thus allowing a physician orother caregiver to monitor and treat a patient from a distant locationand/or allowing access to various treatment resources from the one ormore remote locations. The illustrated remote device includes a userinterface 3092.

FIG. 31 illustrates a system embodiment in which an IMD 3193 is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 3194positioned to stimulate a vagus nerve. According to various embodiments,neural stimulation lead(s) 3194 are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some vagus nerve stimulation lead embodiments areintravascularly fed into a vessel proximate to the neural target, anduse electrode(s) within the vessel to transvascularly stimulate theneural target. For example, some embodiments stimulate the vagus usingelectrode(s) positioned within the internal jugular vein. Otherembodiments deliver neural stimulation to the neural target from withinthe trachea, the laryngeal branches of the internal jugular vein, andthe subclavian vein. The neural targets can be stimulated using otherenergy waveforms, such as ultrasound and light energy waveforms. Otherneural targets can be stimulated, such as cardiac nerves and cardiac fatpads. The illustrated system includes leadless ECG electrodes on thehousing of the device. These ECG electrodes 3195 are capable of beingused to detect heart rate, for example. Various embodiments includelead(s) positioned to provide a CRM therapy to a heart, and with lead(s)positioned to stimulate and/or inhibit neural traffic at a neuraltarget, such as a vagus nerve, according to various embodiments.

FIG. 32 illustrates a system embodiment that includes an implantablemedical device (IMD) 3296 with satellite electrode(s) 3297 positioned tostimulate at least one neural target. The satellite electrode(s) areconnected to the IMD, which functions as the planet for the satellites,via a wireless link. Stimulation and communication can be performedthrough the wireless link. Examples of wireless links include RF linksand ultrasound links. Examples of satellite electrodes includesubcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes. Various embodiments include satellite neural stimulationtransducers used to generate neural stimulation waveforms such asultrasound and light waveforms. The illustrated system includes leadlessECG electrodes on the housing of the device. These ECG electrodes 3298are capable of being used to detect heart rate, for example. Variousembodiments include lead(s) positioned to provide a CRM therapy to aheart, and with satellite transducers positioned to stimulate/inhibit aneural target such as a vagus nerve, according to various embodiments.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. For example,various embodiments combine two or more of the illustrated processes.Two or more sensed parameters can be combined into a composite parameterused to provide a desired neural stimulation (NS) or anti-hypertension(AHT) therapy. In various embodiments, the methods provided above areimplemented as a computer data signal embodied in a carrier wave orpropagated signal, that represents a sequence of instructions which,when executed by a processor cause the processor to perform therespective method. In various embodiments, methods provided above areimplemented as a set of instructions contained on a computer-accessiblemedium capable of directing a processor to perform the respectivemethod. In various embodiments, the medium is a magnetic medium, anelectronic medium, or an optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. A method for treating a patient, comprising: activating a baroreflexsystem of the patient with a baroreflex activation device according to abaroreflex activation therapy; establishing a threshold range for aparameter indicative of a physiological condition; monitoring theparameter; and adjusting the baroreflex therapy in response to a valueof the monitored parameter if the parameter value is outside of thethreshold range.
 2. The method of claim 1, wherein the threshold rangeis stored in a memory of the baroreflex activation device.
 3. The methodof claim 1, further comprising comparing a value of the monitoredparameter to the threshold range of the parameter.
 4. The method ofclaim 3, wherein the adjusting comprises discontinuing the baroreflexactivation therapy if the monitored parameter is outside of thethreshold range.
 5. The method of claim 3, wherein the adjustingcomprises discontinuing the baroreflex therapy if the value of themonitored parameter is below the parameter threshold range.
 6. Themethod of claim 3, further comprising continuing the baroreflex therapyif the value of the monitored parameter is at or above the thresholdrange.
 7. The method of claim 3, wherein the monitoring of the monitoredparameter continues and the parameter value is compared to the thresholdrange to determine whether baroreflex activation therapy shouldcontinue.
 8. The method of claim 5, wherein the monitoring of themonitored parameter continues and the parameter value is compared to thethreshold range to determine whether baroreflex activation therapyshould resume.
 9. The method of claim 8, wherein the therapy is resumedonce the value of the parameter is at or above the threshold range. 10.The method of claim 1, wherein the baroreflex activation therapycontinues as long as the value of the monitored parameter is greaterthan or equal to the threshold range.
 11. The method of claim 1, whereinthe activation of the baroreflex system comprises activating at leastone of a baroreceptor, one or more nerves emanating from a baroreceptor,and a carotid nerve.
 12. The method of claim 1, wherein the activationof the baroreflex system comprises activating at least one of abaroreceptor, a mechanoreceptor, a pressoreceptor, or another receptorwhich affects blood pressure, nervous system activity, or neurohormonalactivity in a manner analogous to baroreceptors in the arterialvasculature.
 13. The method of claim 1, wherein the activation of thebaroreflex system comprises activating at least one of an afferent nerveemanating from a baroreceptor, a baroreceptor, a mechanoreceptor, apressoreceptor, or another receptor which affects blood pressure,nervous system activity, or neurohormonal activity in a manner analogousto baroreceptors in the arterial vasculature.
 14. The method of claim 1,wherein the baroreflex activation therapy comprises activating abaroreceptor located in at least one of a carotid sinus, aortic arch,heart, common carotid artery, subclavian artery, and brachiocephalicartery.
 15. The method of claim 1, wherein the baroreflex activationtherapy comprises activating a baroreceptor located in at least one ofan inferior vena cava, superior vena cava, portal vein, jugular vein,subclavian vein, iliac vein, and femoral vein.
 16. The method of claim1, wherein the baroreflex activation device is implanted in the patient.17. The method of claim 1, wherein the activation comprises at least oneof electrical activation, mechanical activation, thermal activation,chemical activation, and biological activation.
 18. The method of claim1, wherein the parameter comprises any one or more of heart rate, bloodpressure, ECG, oxygen saturation, blood pH, activity level, proneposture, supine posture, core body temperature, respiration rate,respiration depth, and blood CO2 level.
 19. The method of claim 1,wherein the baroreflex therapy comprises a plurality of therapy regimensat least one of which provides therapy at substantially no energy to thepatient.
 20. The method of claim 1, wherein the therapy regimencomprises at least one or more intensity regimens responsive to one ormore characteristics of pulses generated by the baroreflex activationdevice.
 21. The method of claim 20, wherein the pulse characteristicincludes one or more of duty cycle, pulse amplitude, pulse width, pulsefrequency, pulse separation, pulse waveform, pulse polarity, and pulsephase.
 22. The method of claim 1, wherein the monitoring of thepatient's condition comprises sensing the physiological response withone or more sensors over a period of time.
 23. The method of claim 1,wherein the monitored parameter comprises heart rate.
 24. The method ofclaim 1, wherein the monitored parameter comprises blood pressure. 25.The method of claim 22, wherein, the sensing is performed by a devicecomprising any one or more of extracardiac electrocardiogram,intracardiac electrocardiogram, pressure sensor, and accelerometer. 26.The method of claim 22, wherein, the activation of the baroreflexactivation device is controllable by at least one of the patient and thehealthcare provider.
 27. The method of claim 1, wherein, the monitoringof the parameter comprises measuring at least one electrical potentialdifference occurring within the body.
 28. The method of claim 1,wherein, the monitoring of the parameter comprises measuring a voltagedifference between a first conductive element of the baroreflexactivation therapy device and a second conductive element of thebaroreflex activation device.
 29. The method of claim 28, wherein thefirst conductive element comprises an electrode of the baroreflexactivation device and the second conductive element comprises aconductive housing of the baroreflex activation device.
 30. The methodof claim 28, wherein the first conductive element comprises a firstelectrode of the baroreflex activation device and the second conductiveelement comprises a second electrode of the baroreflex activationdevice.
 31. The method of claim 28, further comprising repeatedlymeasuring at least one electrical potential difference to obtain adigitized electrocardiogram waveform.
 32. The method of claim 28,further identifying at least one R-wave in the electrocardiogram. 33.The method of claim 32, further comprising measuring a time intervalbetween at least one pair of R-waves.
 34. The method of claim 28,further comprising identifying at least one R-wave peak in theelectrocardiogram.
 35. The method of claim 34, further comprisingmeasuring a time interval between at least one pair of R-wave peaks. 36.The method of claim 1, further comprising repeatedly measuring the valueof the parameter to provide a digitized parameter waveform.
 37. Themethod of claim 36, further comprising repeatedly measuring the value ofthe parameter; comparing the measured value to a second threshold value;and resuming application of baroreflex activation therapy if themeasured value is greater than the second threshold value.
 38. Themethod of claim 37, wherein the second threshold value is different thanthe threshold value.
 39. The method of claim 37, wherein the secondthreshold value is greater than the threshold value.
 40. A method fortreating a patient, comprising: activating a baroreflex system of thepatient with a baroreflex activation device according to a baroreflextherapy comprising a plurality of baroreflex stimulation regimenswherein at least one of the regimens provides therapy at an intensitylevel different from another regimen; establishing a target range for apatient parameter indicative of a physiological condition; establishinga threshold range for the patient parameter; monitoring the patient'sparameter; and adjusting the baroreflex therapy in response to a valueof the monitored parameter if the parameter value is outside of thethreshold range.
 41. The method of claim 40, wherein baroreflex therapyis delivered at an initial intensity level.
 42. The method of claim 40,wherein the parameter is monitored over a period of time.
 43. The methodof claim 40, further comprising comparing the monitored parameter to thethreshold range of the parameter.
 44. The method of claim 40, whereinthe monitored response comprises any one or more of heart rate, bloodpressure, ECG, oxygen saturation, blood pH, activity level, proneposture, supine posture, core body temperature, respiration rate,respiration depth, and blood CO2 level.
 45. The method of claim 40,wherein the at least one or more intensity regimens comprises changingone or more characteristics of pulses generated to activate thebaroreflex system of the patient.
 46. The method of claim 40, whereinthe delivery of the baroreflex therapy is by way of an open loop system,wherein the therapy is controllable by the patient or the healthcareprovider.
 47. The method of claim 40, wherein the delivery of thebaroreflex therapy is by way of a closed loop system, wherein thetherapy is controllable by a pre-programmed instructions.
 48. The methodof claim 40, wherein the monitoring of the patient's condition comprisessensing the parameter with one or more sensors over a period of time.49. The method of claim 45, wherein the pulse characteristic includesone or more of duty cycle, pulse amplitude, pulse width, pulsefrequency, pulse separation, pulse waveform, pulse polarity, and pulsephase.
 50. The method of claim 40, wherein the monitored parametercomprises heart rate.
 51. The method of claim 40, wherein the monitoredparameter comprises blood pressure.
 52. The method of claim 43, furthercomprising discontinuing the baroreflex therapy if the monitoredparameter is outside the threshold range.
 53. The method of claim 43,further comprising comparing the monitored parameter to the parametertarget range if the monitored parameter is greater than the thresholdrange.
 54. The method of claim 52, wherein the patient parameter iscontinuously monitored over a period of time and compared to thethreshold range to determine whether baroreflex therapy should resume.55. The method of claim 53, wherein if the monitored parameter is atleast equal to the target range, baroreflex therapy and the monitoringof the parameter continues.
 56. The method of claim 53, wherein if themonitored parameter is not equal to the target range, the baroreflextherapy is delivered according to a baroreflex activation therapyregimen responsive to the value of the monitored parameter and themonitoring of the parameter continues.
 57. The method of claim 53,wherein if the monitored parameter is greater than the target range, thebaroreflex therapy is delivered according to a regimen deliveringbaroreflex activation therapy at a higher intensity.
 58. The method ofclaim 53, wherein if the monitored parameter is less than the targetrange, the baroreflex therapy is delivered according to a regimendelivering therapy at a lower intensity.
 59. A system for treating apatient, comprising: a therapy circuitry for delivering baroreflexactivation therapy to the patient; a controller circuitry configured forapplying the baroreflex activation therapy to the patient, thecontroller connectable to the therapy circuitry; and a memory circuitryin communication with the controller and configured for storinginformation regarding the baroreflex activation therapy.
 60. The systemof claim 59, wherein the therapy circuitry comprises a pulse generatorconfigured for generating stimulation pulses to activate the baroreflexsystem of the patient, wherein the pulse generator is configured fordelivery of a plurality pulses having different intensity levels. 61.The system of claim 59, wherein the baroreflex activation therapycomprises a plurality of therapy regimens comprising different intensitylevels, wherein at least one of the intensity levels is at or close tozero.
 62. The system of claim 60, wherein the baroreflex activationtherapy includes a plurality therapy regimens at least one of which isdifferent than another regimen.
 63. The system of claim 60, wherein thesystem further comprises at least one electrode assembly.
 64. The systemof claim 63, wherein the electrode assembly is locatable proximate oneor more baroreceptors of the patient.
 65. The system of claim 59,wherein the system further comprises a monitoring circuitry connectableto the controller circuitry.
 66. The system of system 65, wherein thesystem further comprises a sensor connectable to the monitoringcircuitry and which is configured for sensing of the patient parameterwhich is indicative of a physiological condition.
 67. The system ofclaim 65, wherein the sensor comprises one or more of extracardiacelectrocardiogram, intracardiac electrocardiogram, pressure sensor, andaccelerometer.
 68. The system of system 66, wherein the controllercircuitry is configured to adjust the baroreflex activation therapybased on information received by way of the sensor.
 69. The system ofclaim 65, further comprising a switching circuitry connectable to themonitoring circuitry and the therapy circuitry for adjusting thebaroreflex activation therapy based on the information received from themonitoring circuitry and the therapy circuitry.
 70. The system of claim69, wherein the switching circuitry is connectable to at least oneelectrode assembly locatable proximate one or more baroreceptors of thepatient.
 71. The system of claim 59, wherein the system is housed withina single housing.
 72. The system of claim 59, wherein the system isimplantable in the patient.
 73. The system of claim 59, wherein thesystem is further configured for communication with other devicescomprising: cardiac rhythm management devices comprising cardiacresynchronization therapy (“CRT”) devices, cardioverters,defibrillators, pacemakers, and combinations thereof.
 74. A system fortreating a patient, comprising: a therapy circuitry for providingbaroreflex activation therapy (BAT) to a body of a patient; a monitoringcircuitry that is capable of measuring a biopotential within the body ofthe patient for producing an electrocardiogram signal; a switchingcircuitry coupled to the therapy circuitry and the measurementcircuitry; and a control circuitry coupled to the switching circuitry,the control circuitry configured for directing the switching circuitryto periodically connect one or more electrodes to the therapy circuitryfor providing baroreflex activation therapy (BAT) to the body of thepatient, and the control circuitry configured for directing theswitching circuitry to periodically connect the one or more electrodesto the monitoring circuitry for measuring the biopotential within thebody of the patent for producing the electrocardiogram signal.
 75. Abaroreflex activation therapy (BAT) system, comprising: a therapycircuitry connected to a first therapy terminal and a second therapyterminal for producing a baroreflex activation therapy signal; ameasurement circuitry that is capable of measuring a voltage between afirst measurement terminal and a second terminal; and a switchingcircuitry connected to the first measurement terminal, the secondterminal, the first therapy terminal, and the second therapy terminal;the switching circuitry selectively coupling a first electrode and asecond electrode to the first therapy terminal and the second therapyterminal, respectively, for providing baroreflex activation therapy to abody of a patient.
 76. The system of claim 75, wherein the switchingcircuitry selectively couples the first electrode and a conductivehousing of the BAT system to the first measurement terminal and thesecond measurement terminal, respectively, for measuring an electricpotential difference within the body of the patient.
 77. The system ofclaim 76, wherein the conductive housing comprises a hermetically sealedhousing defining an interior.
 78. The system of claim 77, wherein thetherapy circuitry, the measurement circuitry, and the switchingcircuitry are all disposed in the interior of the housing.
 79. Thesystem of claim 75, wherein the switching circuitry selectively couplesthe first electrode and a third electrode to the first measurementterminal and the second measurement terminal, respectively, formeasuring an electric potential difference within the body of thepatient.
 80. A baroreflex activation therapy device, comprising: amemory storing a threshold value associated with a physiologicalparameter of a patient; a therapy circuitry for delivering baroreflexactivation therapy to a body of the patient; a sensor for measuring avalue of a physiological parameter of the patient; and a disablecircuitry that disconnects the therapy circuitry from at least onepatient electrode if the measured value is below the threshold value.81. The system of claim 80, wherein the sensor comprises a pressuresensor.
 82. The system of claim 80, wherein the sensor comprises ameasurement circuitry connected to one or more electrodes for measuringa biopotential in the body of the patient.
 83. A baroreflex activationtherapy (BAT) system, comprising: a therapy circuitry connected to afirst therapy terminal and a second therapy terminal for producing abaroreflex activation therapy signal; a controller connected to thetherapy circuitry; a sensor connected to the controller; a switchingcircuitry connected to the controller; and the switching circuitry beingconnected to the first sensor terminal and the second terminal, whereinthe switching circuitry selectively couples a first electrode and asecond electrode to the first therapy terminal and the second therapyterminal, respectively, for providing baroreflex activation therapy to abody of a patient.
 84. The system of claim 83, wherein the sensorcomprises a pressure sensor.